Composition and method for the treatment or prophylaxis of viral infections using modified oligodeoxyribonucleotides

ABSTRACT

A composition and method of treatment or prophylaxis of a viral infection in a mammal, such as a human, are provided. The compounds in the composition and which are administered in the method, are oligodeoxyribonucleic acid derivatives of the formula (1): ##STR1## wherein R 1 , R 2  and R 3  are hydrogen atoms, alkyl groups, aryl groups, and anthraquinonyl groups; Z is carbon or silicon; or R 2 , R 3  and Z together represent fluorenyl or xanthenyl; R 4  is a hydrogen atom, an alkyl group or an aryl group; Y 1 , Y 3  and Y 4  are oxygen, sulfur or &gt;NH; Y 2  is oxygen, sulfur, &gt;NH, alkylene or phenylene; X is an alkylene group; m and n are each 0 to 10; and B is an oligodeoxyribonucleotide of a chain length of 3 to 9, or salts thereof.

This is a division of application Ser. No. 08/393,510 filed Feb. 23,1995, now U.S. Pat. No. 5,674,856, which is a continuation ofapplication Ser. No. 08/189,046 filed Jan. 31, 1994 (abandoned).

BACKGROUND OF THE INVENTION

The present invention relates to a series of new modifiedoligodeoxyribonucleotides which have excellent anti-viral activity. Theinvention also provides methods and compositions using theseoligodeoxyribonucleotides for the therapy and prophylaxis of viralinfections and for inhibiting the proliferation of neoplastic cells. Theinvention also provides processes for the preparation of thesecompounds. The compounds of the present invention are particularlyeffective against the Human Immunodeficiency Virus (HIV), now generallyaccepted to be the cause of AIDS.

It is known that oligodeoxyribonucleotides (anti-senseoligodeoxyribonucleotides) having a sequence complementary to a geneinhibit the functional expression of that gene. Also it has beenreported that anti-sense oligodeoxyribonucleotides complementary to avirus gene or oncogene can inhibit the replication of the virus or themultiplication of the cell by inhibiting the function of the respectivegenes P. C. Zamecnik, M. L. Stephenson, Proc. Natl. Acad. Sci. USA, 75,(1) 280 (1978) and P. C. Zamecnik, J. Goodchild, Y. Taguchi, Sarin,Proc. Natl. Acad. Sci. USA, 83, (6) 4143 (1986)!.

It has previously been thought that, in order that ananti-sense-oligodeoxyribonucleotide should exhibit the desired activity,the oligodeoxyribonucleotide should be capable of forming a stablehybrid with the target RNA or DNA in vivo and that, accordingly, itshould have a chain length of 15 or more nucleotides. In general,however, synthesize such oligodeoxyribonucleotides in yields andpurities which enable them to be put to practical use. Moreover theanti-sense oligodeoxyribonucleotides do not have sufficient activity toinhibit the replication of the virus or to inhibit the multiplication ofthe cells to enable them to be used for treatment; moreover, thetoxicity of these compounds towards the normal cells of a host isrelatively high.

Although oligodeoxynucleotides having a short chain length are known, ithas previously been considered that they would have poor inhibitoryactivity. As a result, most researchers have concentrated on theinvestigation of oligodeoxyribonucleotides having longer chains thanthose of the present invention. Thus, for example, although PCTApplication No. WO 88/07544 (which is thought to represent the closestprior art to the present invention) includes within its scopeoligonucleotides having as few as 4 base units, in practice, it is clearthat the only materials tested are those having significantly greaternumbers of units, larger than those of the present invention. We havenow found that certain modified oligodeoxyribonucleotides consisting ofvarious base sequences and prepared by introducing various substituentsinto the 5'- and/or 3'-terminals exhibit excellent anti-AIDS virusactivity, and that the toxicity of the nucleotide toward the normalcells of a host animal is low. Moreover, and important practicalconsideration is that the modified oligodeoxyribonucleotides of thepresent invention can readily be synthesized using simple knowntechniques.

BRIEF SUMMARY OF INVENTION

It is, therefore, an object of the present invention to provide a seriesof new modified oligodeoxyribonucleotides.

It is a further and more specific object of the invention to providesuch modified oligodeoxyribonucleotides which have the ability toinhibit the replication of foreign nucleic acids in normal cells andwhich can therefore be used for the treatment and prophylaxis of viralinfections, including AIDS, and tumors.

A related object of the present invention is to provide processes forpreparing the new olgodexyribonucleotide compounds, and intermediatesfor use in the preparative processes.

Other objects and advantages of the invention will become apparent asthe description proceeds.

SUMMARY OF THE INVENTION

The compounds of the present invention are those modifiedoligodeoxyribonucleotides of formula (1): ##STR2## wherein: R₁, R₂ andR₃ are independently selected from the group consisting of hydrogenatoms, alkyl groups having from 1 to 4 carbon atoms, aryl groups asdefined below, and anthraquinonyl groups which are unsubstituted or aresubstituted by at least one substituent preferably selected from thegroup consisting of substituents 1 defined below;

Z represents a carbon atom or a silicon atom;

or

R₂, R₃ and Z together represent a fluorenyl or xanthenyl group;

R₄ represents a hydrogen atom, an unsubstituted alkyl group having from1 to 4 carbon atoms, a substituted alkyl group which has from 1 to 4carbon atoms and which is substituted by at least one substituentpreferably selected from the group consisting of substituents 2 definedbelow, an aryl group as defined below, or an aralkyl group as definedbelow;

Y₁, Y₃ and Y₄ are independently selected from the group consisting ofoxygen atoms, sulfur atoms and groups of formula >NH;

Y₂ represents an oxygen atom, a sulfur atom, a group of formula >NH, analkylene group having from 1 to 4 carbon atoms, or a phenylene group;

X represents an unsubstituted alkylene group having from 1 to 10 carbonatoms, or an alkylene group which has from 1 to 10 carbon atoms andwhich is substituted by at least one hydroxy group;

m and n is each independently 0 or an integer from 1 to 10; and

B represents an oligodeoxyribonucleotide having a chain length of from 3to 9;

said aryl group is an aromatic carbocyclic group which has from 6 to 20ring carbon atoms and which is unsubstituted or is substituted by atleast one substituent selected from the group consisting of substituents1 defined below;

said aralkyl group is an alkyl group which has from 1 to 4 carbon atomsand which is substituted by at least one aryl group as defined above;

said substituents 1 are selected from the group consisting of alkylgroups having from 1 to 4 carbon atoms, haloalkyl groups having from 1to 4 carbon atoms, halogen atoms, nitro groups, cyano groups, aminogroups, alkoxy groups having from 1 to 4 carbon atoms, alkylthio groupshaving from 1 to 4 carbon atoms, aryl groups as defined above, aryloxygroups in which the aryl part is as defined above, and aralkyloxy groupsin which the aralkyl part is as defined above, provided that, where saidsubstituent 1 represents an aryl group or a group containing an arylgroup which is substituted by a further aryl group or group or groupcontaining an aryl group, that further group is not itself substitutedby an aryl group or a group containing an aryl group; and

said substituents 2 are selected from the group consisting of aminogroups, alkoxy groups having from 1 to 4 carbon atoms, and halogenatoms.

The invention also provides a composition for the treatment orprophylaxis of viral infections, which comprises an effective amount ofat least one oligodeoxyribonucleotide, wherein saidoligodeoxyribonucleotide is a compound of formula (1) as defined above.

The invention also provides a method for the treatment or prophylaxis ofa viral infection in a mammal, which may be human, which methodcomprises administering to said mammal an effective amount of at leastone oligodeoxyribonucleotide, wherein said oligodeoxyribonucleotide is acompound of formula (1) as defined above.

The invention also provides processes and intermediates for preparingthe compounds of the present invention, which processes are described ingreater detail hereafter.

DETAILED DESCRIPTION OF INVENTION

The new modified oligodeoxyribonucleotides of the present invention arenormally provided in a form free from reaction by-products.

In the compounds of the present invention, where R₁, R₂ or R₃ representsan alkyl group, this may be a straight or branched chain alkyl grouphaving from 1 to 4 carbon atoms, and examples include the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups. Ofthese, we prefer the t-butyl group.

Where R₁, R₂ or R₃ represents an aryl group, this may be an aromaticcarbocyclic group which has from 6 to 20 ring carbon atoms, morepreferably from 6 to 16 ring carbon atoms, still more preferably from 6to 10 ring carbon atoms and most preferably 6 or 10 carbon atoms, andwhich is unsubstituted or is substituted by at least one substituentselected from the group consisting of substituents 1 defined andexemplified below. Examples of the unsubstituted groups include thephenyl, 1-naphthyl, 2-naphthyl, phenanthren-4-yl, anthracen-9-yl,anthracen-2-yl and pyrenyl groups. Of these, the more preferred groupsare the naphthyl and phenyl groups, the phenyl group being mostpreferred. The substituted groups may be any of these groups and may besubstituted by one or more of substituents 1, defined above andexemplified below. There is no particular restriction on the number ofsubstituents, except such as may be imposed by the number ofsubstitutable positions (for example, 5 in the case of the phenyl groupor 7 in the case of the naphthyl groups) and possibly by stericconstraints. Most commonly, however, we prefer from 1 to 5 suchsubstituents, more preferably from 1 to 3 and most preferably 1 or 2,substituents. Specific examples of substituents 1 include:

alkyl groups having from 1 to 4 carbon atoms, such as the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, ofwhich we prefer the methyl and t-butyl groups;

haloalkyl groups having from 1 to 4 carbon atoms, such as thefluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-iodoethyl,3-chloropropyl and 4-fluorobutyl and 6-iodohexyl groups, of which weprefer the 2,2,2-trichloroethyl and trifluoromethyl groups;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms,of which the chlorine and fluorine atoms are preferred;

nitro groups, cyano groups, amino groups;

alkoxy groups having from 1 to 4 carbon atoms, such as the methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxygroups, of which we prefer the methoxy and t-butoxy groups;

alkylthio groups having from 1 to 4 carbon atoms, such as themethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio and t-butylthio groups, of which we preferthe methylthio and t-butylthio groups;

aryl groups as defined and exemplified above, and most preferably thephenyl group;

aryloxy groups in which the aryl part is as defined and exemplifiedabove, and most preferably the phenoxy group;

and aralkyloxy groups in which the aralkyl part is as defined above,such as the benzyloxy and dibenzyloxybenzyloxy particularly the3,5-dibenzyloxybenzyloxy group!.

It should be observed that, whilst an aryl group (or a group containingan aryl group) may itself be substituted by a further such group, alimit is imposed herein on such further substitution, in that, wheresaid substituent 1 represents an aryl group or a group containing anaryl group which is substituted by a further aryl group or group orgroup containing an aryl group, that further group is not itselfsubstituted by an aryl group or a group containing an aryl group.

Specific examples of such substituted aryl groups include the4-methylphenyl, 4-t-butylphenyl, 2-phenylphenyl, 4-phenylphenyl,4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,4-iodophenyl, 2,4-difluorophenyl, 4-nitrophenyl, 4-t-butoxyphenyl,4-methoxyphenyl, 4-ethoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl,2-benzyloxyphenyl, 4-benzyloxyphenyl, 3,4-dibenzyloxyphenyl,3,5-dibenzyloxyphenyl and 3,5-bis(3,5-dibenzyloxybenzyloxy)phenylgroups. Of the substituted and unsubstituted aryl groups, we prefer thephenyl, 4-methoxyphenyl, 3,4-dibenzyloxyphenyl, 3,5-dibenzyloxyphenylgroup and 3,5-bis(3,5-dibenzyloxybenzyloxy)phenyl groups.

Where R₁, R₂ or R₃ represents an anthraquinonyl group, this may beunsubstituted or it may be substituted by one or more of substituents 1,defined and exemplified above. Where the group is substituted, it may besubstituted by at least one substituent selected from the groupconsisting of substituents 1 defined and exemplified above. There is noparticular restriction on the number of substituents, except such as maybe imposed by the number of substitutable positions and possibly bysteric constraints. We prefer from 1 to 5 such substituents, morepreferably from 1 to 3 and most preferably 1, substituents. Examples ofsuch groups include the 9,10-anthraquinon-1-yl, 9,10-anthraquinon-2-yl,4-methyl-9,10-anthraquinon-1-yl, 5-methoxy-9,10-anthraquinon-1-yl,7-chloro-9,10-anthraquinon-1-yl, 8-fluoro-9,10-anthraquinon-2-yl,6-ethyl-9,10-anthraquinon-2-yl, 8-ethoxy-9,10-anthraquinon-2-yl and6-hydroxy-9,10-anthraquinon-1-yl groups. Of these, we prefer theunsubstituted anthraquinonyl groups.

Alternatively, R₂, R₃, and Z may together represent a fluorenyl orxanthenyl group, in which case this is preferably a fluoren-9-yl orxanthen-9-yl group.

Where R₄ represents an alkyl group, this may be any of those exemplifiedabove in relation to R₁ etc., but may be unsubstituted or substituted.If substituted, it is substituted by at least one of substituents 2,defined above. Examples of such substituents 2 include amino groups,alkoxy groups having from 1 to 4 carbon atoms and halogen atoms, whichmay be as exemplified above in relation to substituents 1, above.Specific examples of such substituted and unsubtituted alkyl groupsinclude the methyl, ethyl, 2-aminoethyl, 2-methoxyethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and t-butyl group. Of these, weprefer the methyl, ethyl, 2-aminoethyl, 2-methoxyethyl and propylgroups.

Where R₄ represents an aryl group, this may be any of the aryl groupsexemplified above in relation to R₁ etc., and may be a substituted orunsubstituted group. Examples of such groups include: the phenyl group;alkylphenyl groups, such as the 2-methylphenyl or 3-ethylphenyl group;halogenated phenyl groups, such as the 2-fluorophenyl, 2-chlorophenyl,4-chlorophenyl, 2-bromophenyl or 2-iodophenyl group; nitrophenyl groups,such as the 2-nitrophenyl or 4-nitrophenyl group; alkoxyphenyl groups,such as the 4-methoxyphenyl or 4-ethoxyphenyl group; alkyithiophenylgroups, such as the 4-methylthiophenyl or 4-ethylthiophenyl group; andthe naphthyl, phenanthrenyl, anthracenyl and pyrenyl groups. Of these,we prefer then unsubstituted phenyl, halogenated phenyl and nitrophenylgroups.

Where R₄ represents an aralkyl group, this is an alkyl group which hasfrom 1 to 4 carbon atoms and which is substituted by at least one (andpreferably 1, 2 or 3, more preferably 1) aryl groups which may be asdefined and exemplified above. Examples of such groups include thebenzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl,fluorobenzyl, chlorobenzyl, bromobenzyl, chloronaphthylmethyl,indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl,triphenylmethyl, 1-phenethyl, 2-phenethyl, 2,2-diphenylethyl,2,2,2-triphenylethyl, 3,3,3-triphenylpropyl, 1-naphthylethyl,2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl,2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl,2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl,2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl,1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl,5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl,4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl,2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and6-naphthylhexyl groups. Of these, we prefer an unsubstituted benzyl or2-phenethyl group.

Where Y₂ represents a alkylene group, this may be a methylene, ethylene,propylene, tetramethylene or pentamethylene group. Of these, we prefer amethylene group.

Y₁, Y₃ and Y₄ each preferably represents an oxygen atom.

Y₂ represents preferably an oxygen or sulfur atom.

Z preferably represents a carbon atom.

Where X represents a straight or branched chain optionally substitutedwith a hydroxy group, examples include a methylene, methylmethylene,ethylene, propylene, tetramethylene, methylethylene,1-methyltrimethylene, 2-methyltrimethylene, 2-methyltetramethylene,3-methyltrimethylene, pentamethylene, hexamethylene, heptamethylene,octamethylene, nonamethylene, decamethylene, 2-hydroxytrimethylene or2-hydroxytetramethylene group. Of these, we prefer a methylene,methylmethylene, ethylene, or methylethylene group.

The preferred values for each of m and n is an integer of 0 to 6. Weparticularly prefer that m is an integer of 0 to 4.

The oligodeoxyribonucleotide represented by B preferably has a chainlength of 4 to 8; more preferably a chain length of 5 or 6. Moreover, itis preferred that the fourth deoxyribonucleotide from the 5'-terminalend is guaninedeoxyribonucleotide.

The typical preferred illustrative oligodeoxyribonucleotides are thosein the following "α group" and the more preferred ones are those in thefollowing "β group", where the abbreviations used in the following α andβ groups have the following significance:

A: adeninedeoxyribonucleotide;

G: guaninedeoxyribonucleotide;

C: cytosinedeoxyribonucleotide;

T: thyminedeoxyribonucleotide;

mC: 5-methylcytosinedeoxyribonucleotide; and

mG: O⁶ -methylguaninedeoxyribonucleotide. The term "left end" signifiesa 5'-terminal end and the term "right end" signifies a 3'-terminal end,subject to the proviso that there is no hydroxy group at both the 5'-and 3'-terminal ends of each oligodeoxyribonucleotide.

"α group": TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG,TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG, GGGCGGGGC,TAGGAGG, TGGGAGGT, TGGGCGCAG, CCG, TCGGAGG, TGmCGAGG, CTGGGAGG, TGG,TGGGAmGG, TGGGAGA, AATGGGAGG, TTGGGG, TGGGGG, CGGGG, CGCGG, CGGGT,TGGGC, TGGGT.

"β group": TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG,TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG, TTGGGG,TGGGGG, CGGGG, CGCGG.

A preferred group of formula: R₁ R₂ R₃ Z--Y₁, at the 5'-terminal end isexemplified by a triphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy,3,5-(dibenzyloxy)benzyloxy, 3,5-bis3,5-(dibenzyloxy)benzyloxy!benzyloxy, tert-butyldiphenylsilyloxy,phenylfluorenyloxy or phenylxanthenyloxy group; more preferably atriphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy or3,5-(dibenzyloxy)benzyloxy group.

A preferred group of formula: P(O)(Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H atthe 3'-terminal end is exemplified by a hydrogen atom, amethylphosphoryl, 2-chlorophenylphosphoryl, -O-methylthiophosphoryl,methylphosphonyl, methylthiophosphonyl, phenylphosphonyl,2-hydroxyethylphosphoryl, -O-(2-hydroxyethyl)thiophosphoryl,phenylphosphoryl, 4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl or -O-ethylthiophosphorylgroup; more preferably a hydrogen atom, a methylphosphoryl,2-chlorophenylphosphoryl, -O-methylthiophosphoryl, methylphosphonyl,methylthiophosphonyl, phenylphosphonyl, 2-hydroxyethylphosphoryl or-O-(2-hydroxyethyl)thiophosphoryl group.

Collectively, the preferred compounds of the present invention are thosein which:

(1) the chain length of B is 4 to 8;

(2) the chain length of B is 5 or 6;

(3) the chain length of B is 4 to 8, and the fourth deoxyribonucleotidefrom the 5'-terminal of B is guaninedeoxyribonuleotide;

(4) the group of formula: R₁ R₂ R₃ Z--Y₁, at the 5'-terminal end is atriphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy,3,5-(dibenzyloxy)benzyloxy, 3,5-bis3,5-(dibenzyloxy)benzyloxy!benzyloxy, tert-butyldiphenylsilyloxy,phenylfluorenyloxy or phenylxanthenyloxy group; a group of formula:P(O)(Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H, at the 3'-terminal end is ahydrogen atom, a methylphosphoryl, 2-chlorophenylphosphoryl,-O-methylthiophosphoryl, methylphosphonyl, methylthiophosphonyl,phenylphosphonyl, 2-hydroxyethylphosphoryl,-O-(2-hydroxyethyl)thiophosphoryl, phenylphosphoryl,4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl or -O-ethylthiophosphorylgroup; and B is TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG,TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG, GGCGGGGC,TAGGAGG, TGGGAGGT, TGGGCGCAG, CCG, TCGGAGG, TGmCGAGG, CTGGAGG, TGG,TGGGAmGG, TGGGAGA, AATGGGAGG, TTGGGG, TGGGGG, CGGGG, CGCGG, CGGGT, TGGGCor TGGGT;

(5) the group of formula: R₁ R₂ R₃ Z--Y₁, at the 5'-terminal end is atriphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy,3,5-(dibenzyloxy)benzyloxy, 3,5-bis3,5-(dibenzyloxy)benzyloxy!benzyloxy, tert-butyldiphenylsilyloxy,phenylfluorenyloxy or phenylxanthenyloxy group; a group of formula:P(O)(Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H at the 3'-terminal end is ahydrogen atom, a methylphosphoryl, 2-chlorophenylphosphoryl,-O-methylthiophosphoryl, methylphosphonyl, methylthiophosphonyl,phenylphosphonyl, 2-hydroxyethylphosphoryl,-O-(2-hydroxyethyl)thiophosphoryl, phenylphosphoryl,4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl or -O-ethylthiophosphorylgroup; and B is TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG,TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG, TTGGGG,TGGGGG, CGGGG or CGCGG;

(6) the group of formula: R₁ R₂ R₃ Z--Y₁, at the 5'-terminal end is atriphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy,3,5-(dibenzyloxy)benzyloxy, 3,5-bis3,5-(dibenzyloxy)benzyloxy!benzyloxy, tert-butyldiphenylsilyloxy,phenylfluorenyloxy or phenylxanthenyloxy group; a group of formula:P(O)(Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H at the 3'-terminal end is ahydrogen atom, a methylphosphoryl, 2-chlorophenylphosphoryl,-O-methylthiophosphoryl, methylphosphonyl, methylthiophosphonyl,phenylphosphonyl, 2-hydroxyethylphosphoryl or-O-(2-hydroxyethyl)thiophosphoryl group; and B is TGGGAG, TGGGA, TGGGG,TGGG, TGGGAGG, CGGGAGG, TTGGAGG, TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG,mCGmCGAGG, CTGGGAGG, TTGGGG, TGGGGG, CGGGG or CGCGG;

(7) the group of formula: R₁ R₂ R₃ Z--Y₁ at the 5'-terminal end is atriphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy or3,5-(dibenzyloxy)benzyloxy group; a group of formula: (P(O)(Y₂ R₄)--Y₃--(X--Y₄)_(n) !_(m) H at the 3'-terminal end is a hydrogen atom, amethylphosphoryl, 2-chlorophenylphosphoryl, -O-methylthiophosphoryl,methylphosphonyl, methylthiophosphonyl, phenylphosphonyl,2-hydroxyethylphosphoryl, -O-(2-hydroxyethyl)thiophosphoryl,phenylphosphoryl, 4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl or -O-ethylthiophosphorylgroup; and B is TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG,TTGGGAGG TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG, TTGGGG,TGGGGG, CGGGG or CGCGG;

(8) the group of formula: R₁ R₂ R₃ Z--Y₁, at the 5'-terminal end is atriphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy or3,5-(dibenzyloxy)benzyloxy group; a group of formula: P(O)(Y₂ R₄)--Y₃--(X--Y₄)_(n) !_(m) H at the 3'-terminal end is a hydrogen atom, amethylphosphoryl, 2-chlorophenylphosphoryl, -O-methylthiophosphoryl,methylphosphonyl, methylthiophosphonyl, phenylphosphonyl,2-hydroxyethylphosphoryl or -O-(2-hydroxyethyl)thiophosphoryl group; andB is TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG, TTGGGAGG,TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG, TTGGGG, TGGGGG, CGGGGor CGCGG.

Examples of the compounds of the present invention are listed inTable 1. Such examples are not to be construed as being limitative ofthe invention.

In the Table, the following abbreviations are used to denote certaingroups:

    ______________________________________                                        2-Anq      anthraquinon-2-yl                                                  2-Ant      anthracen-2-yl                                                     9-Ant      anthracen-9-yl                                                     Bdbbp      3,5-bis 3,5-(dibenzyloxy)benzyloxy!phenyl                          Bu         butyl                                                              tBu        t-butyl                                                            Bz         benzyl                                                             3,4-Dbp    3,4-(dibenzyloxy)phenyl                                            3,5-Dbp    3,5-(dibenzyloxy)phenyl                                            Decm       decamethylene  --(CH.sub.2).sub.10 --!                             Et         ethyl                                                              Ete        ethylene  --CH.sub.2 CH.sub.2 --!                                  Hepm       heptamethylene  --(CH.sub.2).sub.7 --!                             Hexm       hexamethylene  --(CH.sub.2).sub.6 --!                              Hpr        2-hydroxypropylene  --CH.sub.2 C(OH)(CH.sub.3)--!                  Me         methyl                                                             Mee        methylene  --CH.sub.2 --!                                          Nonm       nonamethylene  --(CH.sub.2).sub.9 --!                              Npe        naphthalenyl  e.g. 2-Npe is naphthalen-2-yl or                                1-Npe is naphthalen-1-yl!                                          Octm       octamethylene  --(CH.sub.2).sub.8 --!                              Penm       pentamethylene  --(CH.sub.2).sub.5 --!                             Ph         phenyl                                                             Pha        phenanthrenyl  e.g. 4-Pha is phenanthren-4-yl!                     Phe        1,4-phenylene                                                      Pr         propyl                                                             Pre        propylene  --CH.sub.2 CH(CH.sub.3)--!                              1-Pyr      pyren-1-yl                                                         Tetm       tetramethylene  --(CH.sub.2).sub.4 --!                             Trim       trimethylene  --(CH.sub.2).sub.3 --!                               ______________________________________                                    

In addition, the sequence represented by "B" in formula (1) isidentified by the following code numbers:

    ______________________________________                                         1                TGGGAG                                                       2                TGGGA                                                        3                TGGGG                                                        4                TGGG                                                         5                TGGGAGG                                                      6                CGGGAGG                                                      7                TTGGAGG                                                      8                TTGGGAGG                                                     9                TGCGAGG                                                     10                GGGGAGG                                                     11                mCGGGAGG                                                    12                mCGmCGAGG                                                   13                CTGGGAGG                                                    14                GGGCGGGC                                                    15                TAGGAGG                                                     16                TGGGAGGT                                                    17                TGGGCGCAG                                                   18                CCG                                                         19                TCGGAGG                                                     20                TGmCGAGG                                                    21                GTGGGAGG                                                    22                TGG                                                         23                TGGGAmGG                                                    24                TGGGAGA                                                     25                AATGGGAGG                                                   26                TTGGGG                                                      27                TGGGGG                                                      28                CGGGG                                                       29                CGCGG                                                       30                CGGGT                                                       31                TGGGC                                                       32                TGGGT.                                                      ______________________________________                                    

Also, where a fluorenyl or xanthenyl group is shown in the Table, thisis represented by R₂, R₃ and Z together.

                                      TABLE 1                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sub.1                                                                            R.sub.2                                                                            R.sub.3                                                                            Z Y.sub.1                                                                         Y.sub.2                                                                          R.sub.4                                                                            Y.sub.3                                                                          X     Y.sub.4                                                                          n m B                               __________________________________________________________________________    1  3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 1                               2  3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 1                               3  3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 1                               4  3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 1                               5  3,4-Dbp                                                                            H    H    O O O  Me   S  --    -- 0 1 1                               6  3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 1                               7  3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 1                               8  3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 1                               9  3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 1                               10 3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 1                               11 3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 1                               12 Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 1                               13 Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 1                               14 Ph   Ph   Ph   C O -- --   -- --    -- 0 0 1                               15 Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 1                               16 Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 1                               17 Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 1                               18 Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 1                               19 Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 1                               20 Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 1                               21 Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 1                               22 Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 1                               23 3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 1                               24 3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 1                               25 3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 1                               26 3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 1                               27 3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 1                               28 3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 1                               29 3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 1                               30 3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 1                               31 3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 1                               32 3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 1                               33 3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 1                               34 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 1                               35 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 1                               36 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 1                               37 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 1                               38 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 1                               39 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 1                               40 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 1                               41 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 1                               42 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 1                               43 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 1                               44 4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 1                               45 4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 1                               46 4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 1                               47 4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 1                               48 4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 1                               49 4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 1                               50 4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 1                               51 4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 1                               52 4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 1                               53 4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 1                               54 4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 1                               55 4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 1                               56 tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 1                               57 tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 1                               58 tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 1                               59 tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 1                               60 tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 1                               61 tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 1                               62 tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 1                               63 tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 1                               64 tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 1                               65 tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 1                               66 tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 1                               67 Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 1                               68 Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 1                               69 Ph   Ph   Ph   C S -- --   -- --    -- 0 0 1                               70 Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 1                               71 Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 1                               72 Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 1                               73 Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 1                               74 Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 1                               75 Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 1                               76 Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 1                               77 Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 1                               78 4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 1                               79 4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 1                               80 4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 1                               81 4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 1                               82 4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 1                               83 4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 1                               84 4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 1                               85 4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 1                               86 4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 1                               87 4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 1                               88 4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 1                               89 Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 1                               90 Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 1                               91 Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 1                               92 Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 1                               93 Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 0 1                               94 Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 1                               95 Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 1                               96 Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 1                               97 Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 1                               98 Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 1                               99 Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 1                               100                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 1                               101                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 1                               102                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 1                               103                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 1                               104                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 1                               105                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 1                               106                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 1                               107                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 1                               108                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 1                               109                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 1                               110                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 1                               111                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 2                               112                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 2                               113                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 2                               114                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 2                               115                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 2                               116                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 2                               117                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 2                               118                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 2                               119                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 2                               120                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 2                               121                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 2                               122                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 2                               123                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 2                               124                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 2                               125                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 2                               126                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 2                               127                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 2                               128                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 2                               129                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 2                               130                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 2                               131                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 2                               132                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 2                               133                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 2                               134                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 2                               135                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 2                               136                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 2                               137                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 2                               138                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 2                               139                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 2                               140                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 2                               141                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 2                               142                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 2                               143                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 2                               144                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 2                               145                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 2                               146                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 2                               147                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 2                               148                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 2                               149                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 2                               150                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 2                               151                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 2                               152                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 2                               153                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 2                               154                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 2                               155                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 2                               156                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 2                               157                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 2                               158                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 2                               159                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 2                               160                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 2                               161                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 2                               162                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 2                               163                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 2                               164                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 2                               165                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 2                               166                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 2                               167                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 2                               168                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 2                               169                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 2                               170                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 2                               171                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 2                               172                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 2                               173                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 2                               174                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 2                               175                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 2                               176                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 2                               177                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 2                               178                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 2                               179                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 2                               180                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 2                               181                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 2                               182                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 2                               183                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 2                               184                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 2                               185                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 2                               186                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 2                               187                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 2                               188                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 2                               189                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 2                               190                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 2                               191                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 2                               192                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 2                               193                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 2                               194                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 2                               195                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 2                               196                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 2                               197                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 2                               198                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 2                               199                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 2                               200                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 2                               201                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 2                               202                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 2                               203                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 2                               204                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 2                               205                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 2                               206                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 2                               207                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 2                               208                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 2                               209                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 2                               210                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 2                               211                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 2                               212                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 2                               213                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 2                               214                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 2                               215                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 2                               216                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 2                               217                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 2                               218                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 2                               219                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 2                               220                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 2                               221                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 3                               222                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 3                               223                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 3                               224                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 3                               225                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 3                               226                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 3                               227                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 3                               228                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 3                               229                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 3                               230                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 3                               231                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 3                               232                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 3                               233                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 3                               234                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 3                               235                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 3                               236                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 3                               237                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 3                               238                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 3                               239                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 3                               240                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 3                               241                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 3                               242                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 3                               243                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 3                               244                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 3                               245                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 3                               246                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 3                               247                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 3                               248                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 3                               249                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 3                               250                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 3                               251                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 3                               252                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 3                               253                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 3                               254                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 3                               255                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 3                               256                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 3                               257                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 3                               258                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 3                               259                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 3                               260                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 3                               261                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 3                               262                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 3                               263                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 3                               264                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 3                               265                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 3                               266                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 3                               267                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 3                               268                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 3                               269                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 3                               270                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 3                               271                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 3                               272                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 3                               273                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 3                               274                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 3                               275                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 3                               276                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 3                               277                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 3                               278                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 3                               279                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 3                               280                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 3                               281                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 3                               282                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 3                               283                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 3                               284                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 3                               285                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 3                               286                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 3                               287                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 3                               288                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 3                               289                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 3                               290                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 3                               291                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 3                               292                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 3                               293                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 3                               294                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 3                               295                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 3                               296                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 3                               297                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 3                               298                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 3                               299                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 3                               300                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 3                               301                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 3                               302                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 3                               303                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 3                               304                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 3                               305                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 3                               306                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    0  --    -- 0 1 3                               307                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 3                               308                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 3                               309                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 3                               310                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 3                               311                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 3                               312                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 3                               313                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 3                               314                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 3                               315                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 3                               316                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 3                               317                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 3                               318                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 3                               319                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 3                               320                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 3                               321                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 3                               322                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 3                               323                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 3                               324                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 3                               325                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 3                               326                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 3                               327                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 3                               328                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 3                               329                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 3                               330                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 3                               331                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 4                               332                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 4                               333                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 4                               334                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 4                               335                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 4                               336                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 4                               337                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 4                               338                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 4                               339                                                                              314-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 4                               340                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 4                               341                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 4                               342                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 4                               343                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 4                               344                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 4                               345                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 4                               346                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 4                               347                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 4                               348                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 4                               349                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 4                               350                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 4                               351                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 4                               352                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 4                               353                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 4                               354                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 4                               355                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 4                               356                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 4                               357                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 4                               358                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 4                               359                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 4                               360                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 4                               361                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 4                               362                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 4                               363                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 4                               364                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 4                               365                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 4                               366                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 4                               367                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 4                               368                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 4                               369                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 4                               370                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 4                               371                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 4                               372                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 4                               373                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 4                               374                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 4                               375                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 4                               376                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 4                               377                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 4                               378                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 4                               379                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 4                               380                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 4                               381                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 4                               382                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 4                               383                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 4                               384                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 4                               385                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 4                               386                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 4                               387                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 4                               388                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 4                               389                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 4                               390                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 4                               391                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 4                               392                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 4                               393                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 4                               394                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 4                               395                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 4                               396                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 4                               397                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 4                               398                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 4                               399                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 4                               400                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 4                               401                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 4                               402                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 4                               403                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 4                               404                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 4                               405                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 4                               406                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 4                               407                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 4                               408                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 4                               409                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 4                               410                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 4                               411                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 4                               412                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 4                               413                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 4                               414                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 4                               415                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 4                               416                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 4                               417                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 4                               418                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 4                               419                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 4                               420                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 4                               421                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 4                               422                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 4                               423                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 4                               424                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 4                               425                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 4                               426                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 4                               427                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 4                               428                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 4                               429                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 4                               430                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 4                               431                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 4                               432                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 4                               433                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 4                               434                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 4                               435                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 4                               436                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 4                               437                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 4                               438                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 4                               439                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 4                               440                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 4                               441                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 4                               442                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 5                               443                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 5                               444                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 5                               445                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 5                               446                                                                              314-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 5                               447                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 5                               448                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 5                               449                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 5                               450                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 5                               451                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 5                               452                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 5                               453                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 5                               454                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 5                               455                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 5                               456                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 5                               457                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 5                               458                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 5                               459                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 5                               460                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 5                               461                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 5                               462                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 5                               463                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 5                               464                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 5                               465                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 5                               466                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 5                               467                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 5                               468                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 5                               469                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 5                               470                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 5                               471                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 5                               472                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 5                               473                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 5                               474                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 5                               475                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 5                               476                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 5                               477                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 5                               478                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 5                               479                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 5                               480                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 5                               481                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 5                               482                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 5                               483                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 5                               484                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 5                               485                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 5                               486                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 5                               487                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 5                               488                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 5                               489                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 5                               490                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 5                               491                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 5                               492                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 5                               493                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 5                               494                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 5                               495                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 5                               496                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 5                               497                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 5                               498                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 5                               499                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 5                               500                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 5                               501                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 5                               502                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 5                               503                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 5                               504                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 5                               505                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 5                               506                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 5                               507                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 5                               508                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 5                               509                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 5                               510                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 5                               511                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 5                               512                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 5                               513                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 5                               514                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 5                               515                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 5                               516                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 5                               517                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 5                               518                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 5                               519                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 5                               520                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 5                               521                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 5                               522                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 5                               523                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 5                               524                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 5                               525                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 5                               526                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 5                               527                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 5                               528                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 5                               529                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 5                               530                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 5                               531                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 5                               532                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 5                               533                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 5                               534                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 5                               535                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 5                               536                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 5                               537                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 5                               538                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 5                               539                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 5                               540                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 5                               541                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 5                               542                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 5                               543                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 5                               544                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 5                               545                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 5                               546                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 5                               547                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 5                               548                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 5                               549                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 5                               550                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 5                               551                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 6                               552                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 6                               553                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 6                               554                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 6                               555                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 6                               556                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 6                               557                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 6                               558                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 6                               559                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 6                               560                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 6                               561                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 6                               562                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 6                               563                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 6                               564                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 6                               565                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 6                               566                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 6                               567                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 6                               568                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 6                               569                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 6                               570                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 6                               571                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 6                               572                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 6                               573                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 6                               574                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 6                               575                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 6                               576                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 6                               577                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 6                               578                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 6                               579                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 6                               580                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 6                               581                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 6                               582                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 6                               583                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 6                               584                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 6                               585                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 6                               586                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 6                               587                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 6                               588                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 6                               589                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 6                               590                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 6                               591                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 6                               592                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 6                               593                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 6                               594                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 6                               595                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 6                               596                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 6                               597                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 6                               598                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 6                               599                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 6                               600                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 6                               601                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 6                               602                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 6                               603                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 6                               604                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 6                               605                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 6                               606                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 6                               607                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 6                               608                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 6                               609                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 6                               610                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 6                               611                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 6                               612                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 6                               613                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 6                               614                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 6                               615                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 6                               616                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 6                               617                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 6                               618                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 6                               619                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 6                               620                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 6                               621                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 6                               622                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 6                               623                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 6                               624                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 6                               625                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 6                               626                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 6                               627                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 6                               628                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 6                               629                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 6                               630                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 6                               631                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 6                               632                                                                              4-BzOPh                                                                            H    H    C O O  Me   g  --    -- 0 1 6                               633                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 6                               634                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 6                               635                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 6                               636                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 6                               637                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 6                               638                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 6                               639                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 6                               640                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 6                               641                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 6                               642                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 6                               643                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 6                               644                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 6                               645                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 6                               646                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 6                               647                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 6                               648                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 6                               649                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 6                               650                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 6                               651                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 6                               652                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 6                               653                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 6                               654                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 6                               655                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 6                               656                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 6                               657                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 6                               658                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 6                               659                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 6                               660                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 6                               661                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 7                               662                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 7                               663                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 7                               664                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 7                               665                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 7                               666                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 7                               667                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 7                               668                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 7                               669                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 7                               670                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 7                               671                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 7                               672                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 7                               673                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 7                               674                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 7                               675                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 7                               676                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 7                               677                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 7                               678                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 7                               679                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 7                               680                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 7                               681                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 7                               682                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 7                               683                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 7                               684                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 7                               685                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 7                               686                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 7                               687                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 7                               688                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 7                               689                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 7                               690                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 7                               691                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 7                               692                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 7                               693                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 7                               694                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 7                               695                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 7                               696                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 7                               697                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 7                               698                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 7                               699                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 7                               700                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 7                               701                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 7                               702                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 7                               703                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 7                               704                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 7                               705                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 7                               706                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 7                               707                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 7                               708                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 7                               709                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 7                               710                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 7                               711                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 7                               712                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 7                               713                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 7                               714                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 7                               715                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 7                               716                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 7                               717                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 7                               718                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 7                               719                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 7                               720                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 7                               721                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 7                               722                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 7                               723                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 7                               724                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 7                               725                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 7                               726                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 7                               727                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 7                               728                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 7                               729                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 7                               730                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 7                               731                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 7                               732                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 7                               733                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 7                               734                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 7                               735                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 7                               736                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 7                               737                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 7                               738                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 7                               739                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 7                               740                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 7                               741                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 7                               742                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 7                               743                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 7                               744                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 7                               745                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 7                               746                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 7                               747                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 7                               748                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 7                               749                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 7                               750                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 7                               751                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 7                               752                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 7                               753                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 7                               754                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 7                               755                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 7                               756                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 7                               757                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 7                               758                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 7                               759                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 7                               760                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 7                               761                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 7                               762                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 7                               763                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 7                               764                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 7                               765                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 7                               766                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 7                               767                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 7                               768                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 7                               769                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 7                               770                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 7                               771                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 8                               772                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 8                               773                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 8                               774                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 8                               775                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 8                               776                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 8                               777                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 8                               778                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 8                               779                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 8                               780                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 8                               781                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 8                               782                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 8                               783                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 8                               784                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 8                               785                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 8                               786                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 8                               787                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 8                               788                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 8                               789                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 8                               790                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 8                               791                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 8                               792                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 8                               793                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 8                               794                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 8                               795                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 8                               796                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 8                               797                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 8                               798                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 8                               799                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 8                               800                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 8                               801                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 8                               802                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 8                               803                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 8                               804                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 8                               805                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 8                               806                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 8                               807                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 8                               808                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 8                               809                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 8                               810                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 8                               811                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 8                               812                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 8                               813                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 8                               814                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 8                               815                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 8                               816                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 8                               817                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 8                               818                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 8                               819                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 8                               820                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 8                               821                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 8                               822                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 8                               823                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 8                               824                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 8                               825                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 8                               826                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 8                               827                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 8                               828                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 8                               829                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 8                               830                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 8                               831                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 8                               832                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 8                               833                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 8                               834                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 8                               835                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 8                               836                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 8                               837                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 8                               838                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 8                               839                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 8                               840                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 8                               841                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 8                               842                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 8                               843                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 8                               844                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 8                               845                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 8                               846                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 8                               847                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 8                               848                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 8                               849                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 8                               850                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 8                               851                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 8                               852                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 8                               853                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 8                               854                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 8                               855                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 8                               856                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 8                               857                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 8                               858                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 8                               859                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 8                               860                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 8                               861                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 8                               862                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 8                               863                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 8                               864                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 8                               865                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 8                               866                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 8                               867                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 8                               868                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 8                               869                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 8                               870                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 8                               871                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 8                               872                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 8                               873                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 8                               874                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 8                               875                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 8                               876                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 8                               877                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 8                               878                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 8                               879                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 8                               880                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 8                               881                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 9                               882                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 9                               883                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 9                               884                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 9                               885                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 9                               886                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 9                               887                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 9                               888                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 9                               889                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 9                               890                                                                              3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 9                               891                                                                              3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 9                               892                                                                              Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 9                               893                                                                              Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 9                               894                                                                              Ph   Ph   Ph   C O -- --   -- --    -- 0 0 9                               895                                                                              Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 9                               896                                                                              Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 9                               897                                                                              Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 9                               898                                                                              Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 9                               899                                                                              Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 9                               900                                                                              Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 9                               901                                                                              Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 9                               902                                                                              Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 9                               903                                                                              3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 9                               904                                                                              3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 9                               905                                                                              3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 9                               906                                                                              3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 9                               907                                                                              3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 9                               908                                                                              3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 9                               909                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 9                               910                                                                              3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 9                               911                                                                              3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 9                               912                                                                              3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 9                               913                                                                              3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 9                               914                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 9                               915                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 9                               916                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 9                               917                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 9                               918                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 9                               919                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 9                               920                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 9                               921                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 9                               922                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 9                               923                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 9                               924                                                                              4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 9                               925                                                                              4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 9                               926                                                                              4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 9                               927                                                                              4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 9                               928                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 9                               929                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 9                               930                                                                              4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 9                               931                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 9                               932                                                                              4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 9                               933                                                                              4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 9                               934                                                                              4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 9                               935                                                                              4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 9                               936                                                                              tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 9                               937                                                                              tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 9                               938                                                                              tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 9                               939                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 9                               940                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 9                               941                                                                              tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 9                               942                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 9                               943                                                                              tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 9                               944                                                                              tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 9                               945                                                                              tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 9                               946                                                                              tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 9                               947                                                                              Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 9                               948                                                                              Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 9                               949                                                                              Ph   Ph   Ph   C S -- --   -- --    -- 0 0 9                               950                                                                              Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 9                               951                                                                              Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 9                               952                                                                              Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 9                               953                                                                              Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 9                               954                                                                              Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 9                               955                                                                              Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 9                               956                                                                              Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 9                               957                                                                              Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 9                               958                                                                              4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 9                               959                                                                              4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 9                               960                                                                              4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 9                               961                                                                              4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 9                               962                                                                              4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 9                               963                                                                              4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 9                               964                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 9                               965                                                                              4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 9                               966                                                                              4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 9                               967                                                                              4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 9                               968                                                                              4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 9                               969                                                                              Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 9                               970                                                                              Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 9                               971                                                                              Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 9                               972                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 9                               973                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 9                               974                                                                              Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 9                               975                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 9                               976                                                                              Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 9                               977                                                                              Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 9                               978                                                                              Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 9                               979                                                                              Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 9                               980                                                                              Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 9                               981                                                                              Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 9                               982                                                                              Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 9                               983                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 9                               984                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 9                               985                                                                              Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 9                               986                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 9                               987                                                                              Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 9                               988                                                                              Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 9                               989                                                                              Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 9                               990                                                                              Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 9                               991                                                                              3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 10                              992                                                                              3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 10                              993                                                                              3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 10                              994                                                                              3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 10                              995                                                                              3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 10                              996                                                                              3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 10                              997                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 10                              998                                                                              3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 10                              999                                                                              3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 10                              1000                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 10                              1001                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 10                              1002                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 10                              1003                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 10                              1004                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 10                              1005                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 10                              1006                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 10                              1007                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 10                              1008                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 10                              1009                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 10                              1010                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 10                              1011                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 10                              1012                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 10                              1013                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 10                              1014                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 10                              1015                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 10                              1016                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 10                              1017                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 10                              1018                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 10                              1019                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 10                              1020                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 10                              1021                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 10                              1022                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 10                              1023                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 10                              1024                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 10                              1025                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 10                              1026                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 10                              1027                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 10                              1028                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 10                              1029                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 10                              1030                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 10                              1031                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 10                              1032                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 10                              1033                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 10                              1034                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 10                              1035                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 10                              1036                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 10                              1037                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 10                              1038                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 10                              1039                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 10                              1040                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 10                              1041                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 10                              1042                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 10                              1043                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 10                              1044                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 10                              1045                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 10                              1046                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 10                              1047                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 10                              1048                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 10                              1049                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 10                              1050                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 10                              1051                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 10                              1052                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 10                              1053                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 10                              1054                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 10                              1055                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 10                              1056                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 10                              1057                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 10                              1058                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 10                              1059                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 10                              1060                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 10                              1061                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 10                              1062                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 10                              1063                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 10                              1064                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 10                              1065                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 10                              1066                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 10                              1067                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 10                              1068                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 10                              1069                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 10                              1070                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 10                              1071                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 10                              1072                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 10                              1073                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 10                              1074                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 10                              1075                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 10                              1076                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 10                              1077                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 10                              1078                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 10                              1079                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 10                              1080                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 10                              1081                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 10                              1082                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 10                              1083                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 10                              1084                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 10                              1085                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 10                              1086                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 10                              1087                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 10                              1088                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 10                              1089                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 10                              1090                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 10                              1091                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 10                              1092                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 10                              1093                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 10                              1094                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 10                              1095                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 10                              1096                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 10                              1097                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 10                              1098                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 10                              1099                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 10                              1100                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 10                              1101                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 11                              1102                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 11                              1103                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 11                              1104                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 11                              1105                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 11                              1106                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 11                              1107                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 11                              1108                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 11                              1109                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 11                              1110                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 11                              1111                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 11                              1112                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 11                              1113                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 11                              1114                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 11                              1115                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 11                              1116                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 11                              1117                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 11                              1118                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 11                              1119                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 11                              1120                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 11                              1121                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 11                              1122                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 11                              1123                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 11                              1124                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 11                              1125                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 11                              1126                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 11                              1127                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 11                              1128                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 11                              1129                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 11                              1130                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 11                              1131                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 11                              1132                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 11                              1133                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 11                              1134                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 11                              1135                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 11                              1136                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 11                              1137                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 11                              1138                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 11                              1139                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 11                              1140                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 11                              1141                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 11                              1142                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 11                              1143                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 11                              1144                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 11                              1145                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 11                              1146                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 11                              1147                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 11                              1148                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 11                              1149                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 11                              1150                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 11                              1151                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 11                              1152                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 11                              1153                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 11                              1154                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 11                              1155                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 11                              1156                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 11                              1157                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 11                              1158                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 11                              1159                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 11                              1160                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 11                              1161                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 11                              1162                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 11                              1163                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 11                              1164                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 11                              1165                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 11                              1166                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 11                              1167                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 11                              1168                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 11                              1169                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 11                              1170                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 11                              1171                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 11                              1172                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 11                              1173                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 11                              1174                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 11                              1175                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 11                              1176                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 11                              1177                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 11                              1178                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 11                              1179                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 11                              1180                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 11                              1181                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 11                              1182                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 11                              1183                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 11                              1184                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 11                              1185                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 11                              1186                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 11                              1187                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 11                              1188                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 11                              1189                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 11                              1190                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 11                              1191                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 1 11                              1192                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 11                              1193                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 11                              1194                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 11                              1195                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 11                              1196                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 11                              1197                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 11                              1198                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 11                              1199                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 11                              1200                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 11                              1201                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 11                              1202                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 11                              1203                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 11                              1204                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 11                              1205                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 11                              1206                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 11                              1207                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 11                              1208                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 11                              1209                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 11                              1210                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 11                              1211                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 12                              1212                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 12                              1213                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 12                              1214                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 12                              1215                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 12                              1216                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 12                              1217                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 12                              1218                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 12                              1219                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 12                              1220                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 12                              1221                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 12                              1222                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 12                              1223                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 12                              1224                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 12                              1225                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 12                              1226                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 12                              1227                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 12                              1228                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 12                              1229                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 12                              1230                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 12                              1231                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 12                              1232                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 12                              1233                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 12                              1234                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 12                              1235                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 12                              1236                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 12                              1237                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 12                              1238                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 12                              1239                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 12                              1240                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 12                              1241                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 12                              1242                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 12                              1243                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 12                              1244                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 12                              1245                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 12                              1246                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 12                              1247                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 12                              1248                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 12                              1249                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 12                              1250                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 12                              1251                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 12                              1252                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 12                              1253                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 12                              1254                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 12                              1255                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 12                              1256                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 12                              1257                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 12                              1258                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 12                              1259                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 12                              1260                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 12                              1261                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 12                              1262                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 12                              1263                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 12                              1264                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 12                              1265                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 12                              1266                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 12                              1267                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 12                              1268                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 12                              1269                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 12                              1270                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 12                              1271                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 12                              1272                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 12                              1273                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 12                              1274                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 12                              1275                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 12                              1276                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 12                              1277                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 12                              1278                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 12                              1279                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 12                              1280                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 12                              1281                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 12                              1282                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 12                              1283                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 12                              1284                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 12                              1285                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 12                              1286                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 12                              1287                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 12                              1288                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 12                              1289                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 12                              1290                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 12                              1291                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 12                              1292                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 12                              1293                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 12                              1294                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 12                              1295                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 12                              1296                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 12                              1297                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 12                              1298                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 12                              1299                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 12                              1300                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 12                              1301                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 12                              1302                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 12                              1303                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 12                              1304                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 12                              1305                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 12                              1306                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 12                              1307                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 12                              1308                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 12                              1309                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 12                              1310                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 12                              1311                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 12                              1312                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 12                              1313                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 12                              1314                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 12                              1315                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 12                              1316                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 12                              1317                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 12                              1318                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 12                              1319                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 12                              1320                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 12                              1321                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 13                              1322                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 13                              1323                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 13                              1324                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 13                              1325                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 13                              1326                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 13                              1327                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 13                              1328                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 13                              1329                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 13                              1330                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 13                              1331                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 13                              1332                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 13                              1333                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 13                              1334                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 13                              1335                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 13                              1336                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 13                              1337                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 13                              1338                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 13                              1339                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 13                              1340                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 13                              1341                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 13                              1342                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 13                              1343                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 13                              1344                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 13                              1345                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 13                              1346                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 13                              1347                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 13                              1348                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 13                              1349                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 13                              1350                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 13                              1351                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 13                              1352                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 13                              1353                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 13                              1354                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 13                              1355                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 13                              1356                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 13                              1357                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 13                              1358                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 13                              1359                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 13                              1360                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 13                              1361                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 13                              1362                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 13                              1363                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 13                              1364                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 13                              1365                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 13                              1366                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 13                              1367                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 13                              1368                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 13                              1369                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 13                              1370                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 13                              1371                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 13                              1372                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 13                              1373                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 13                              1374                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 13                              1375                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 13                              1376                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 13                              1377                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 13                              1378                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 13                              1379                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 13                              1380                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 13                              1381                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 13                              1382                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 13                              1383                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 13                              1384                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 13                              1385                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 13                              1386                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 13                              1387                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 13                              1388                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 13                              1389                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 13                              1390                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 13                              1391                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 13                              1392                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 13                              1393                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 13                              1394                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 13                              1395                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 13                              1396                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 13                              1397                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 13                              1398                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 13                              1399                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 13                              1400                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 13                              1401                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 13                              1402                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 13                              1403                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 13                              1404                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 13                              1405                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 13                              1406                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 13                              1407                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 13                              1408                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 13                              1409                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 13                              1410                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 13                              1411                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 13                              1412                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 13                              1413                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 13                              1414                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 13                              1415                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 13                              1416                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 13                              1417                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 13                              1418                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 13                              1419                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 13                              1420                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 13                              1421                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 13                              1422                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 13                              1423                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 13                              1424                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 13                              1425                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 13                              1426                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 13                              1427                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 13                              1428                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 13                              1429                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 13                              1430                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 13                              1431                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 14                              1432                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 14                              1433                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 14                              1434                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 14                              1435                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 14                              1436                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 14                              1437                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 14                              1438                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 14                              1439                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 14                              1440                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 14                              1441                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 14                              1442                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 14                              1443                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 14                              1444                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 14                              1445                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 14                              1446                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 14                              1447                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 14                              1448                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 14                              1449                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 14                              1450                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 14                              1451                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 14                              1452                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 14                              1453                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 14                              1454                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 14                              1455                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 14                              1456                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 14                              1457                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 14                              1458                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 14                              1459                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 14                              1460                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 14                              1461                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 14                              1462                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 14                              1463                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 14                              1464                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 14                              1465                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 14                              1466                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 14                              1467                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 14                              1468                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 14                              1469                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 14                              1470                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 14                              1471                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 14                              1472                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 14                              1473                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 14                              1474                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 14                              1475                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 14                              1476                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 14                              1477                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 14                              1478                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 14                              1479                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 14                              1480                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 14                              1481                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 14                              1482                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 14                              1483                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 14                              1484                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 14                              1485                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 14                              1486                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 14                              1487                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 14                              1488                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 14                              1489                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 14                              1490                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 14                              1491                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 14                              1492                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 14                              1493                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 14                              1494                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 14                              1495                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 14                              1496                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 14                              1497                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 14                              1498                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 14                              1499                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 14                              1500                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 14                              1501                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 14                              1502                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 14                              1503                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 14                              1504                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 14                              1505                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 14                              1506                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 14                              1507                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 14                              1508                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 14                              1509                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 14                              1510                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 14                              1511                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 14                              1512                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 14                              1513                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 14                              1514                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 14                              1515                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 14                              1516                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 14                              1517                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 14                              1518                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 14                              1519                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 14                              1520                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 14                              1521                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 14                              1522                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 14                              1523                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 14                              1524                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 14                              1525                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 14                              1526                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 14                              1527                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 14                              1528                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 14                              1529                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 14                              1530                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 14                              1531                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 14                              1532                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 14                              1533                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 14                              1534                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 14                              1535                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 14                              1536                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 14                              1537                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 14                              1538                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 14                              1539                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 14                              1540                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 14                              1541                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 15                              1542                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 15                              1543                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 15                              1544                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 15                              1545                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 15                              1546                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 15                              1547                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 15                              1548                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 15                              1549                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 15                              1550                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 15                              1551                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 15                              1552                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 15                              1553                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 15                              1554                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 15                              1555                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 15                              1556                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 15                              1557                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 15                              1558                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 15                              1559                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 15                              1560                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 15                              1561                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 15                              1562                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 15                              1563                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 15                              1564                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 15                              1565                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 15                              1566                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 15                              1567                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 15                              1568                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 15                              1569                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 15                              1570                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 15                              1571                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 15                              1572                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 15                              1573                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 15                              1574                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 15                              1575                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 15                              1576                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 15                              1577                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 15                              1578                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 15                              1579                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 15                              1580                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 15                              1581                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 15                              1582                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 15                              1583                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 15                              1584                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 15                              1585                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 15                              1586                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 15                              1587                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 15                              1588                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 15                              1589                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 15                              1590                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 15                              1591                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 15                              1592                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 15                              1593                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 15                              1594                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 15                              1595                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 15                              1596                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 15                              1597                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 15                              1598                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 15                              1599                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 15                              1600                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 15                              1601                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 15                              1602                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 15                              1603                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 15                              1604                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 15                              1605                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 15                              1606                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 15                              1607                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 15                              1608                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 15                              1609                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 15                              1610                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 15                              1611                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 15                              1612                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 15                              1613                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 15                              1614                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 15                              1615                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 15                              1616                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 15                              1617                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 15                              1618                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 15                              1619                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 15                              1620                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 15                              1621                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 15                              1622                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 15                              1623                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 15                              1624                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 15                              1625                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 15                              1626                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 15                              1627                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 15                              1628                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 15                              1629                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 15                              1630                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 15                              1631                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 15                              1632                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 15                              1633                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 15                              1634                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 15                              1635                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 15                              1636                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 15                              1637                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 15                              1638                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 15                              1639                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 15                              1640                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 15                              1641                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 15                              1642                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 15                              1643                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 15                              1644                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 15                              1645                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 15                              1646                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 15                              1647                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 15                              1648                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 15                              1649                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 15                              1650                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 15                              1651                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 16                              1652                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 16                              1653                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 16                              1654                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 16                              1655                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 16                              1656                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 16                              1657                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 16                              1658                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 16                              1659                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 16                              1660                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 16                              1661                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 16                              1662                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 16                              1663                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 16                              1664                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 16                              1665                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 16                              1666                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 16                              1667                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 16                              1668                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 16                              1669                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 16                              1670                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 16                              1671                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 16                              1672                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 16                              1673                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 16                              1674                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 16                              1675                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 16                              1676                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 16                              1677                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 16                              1678                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 16                              1679                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 16                              1680                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 16                              1681                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 16                              1682                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 16                              1683                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 16                              1684                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 16                              1685                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 16                              1686                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 16                              1687                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 16                              1688                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 16                              1689                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 16                              1690                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 16                              1691                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 16                              1692                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 16                              1693                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 16                              1694                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 16                              1695                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 16                              1696                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 16                              1697                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 16                              1698                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 16                              1699                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 16                              1700                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 16                              1701                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 16                              1702                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 16                              1703                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 16                              1704                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 16                              1705                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 16                              1706                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 16                              1707                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 16                              1708                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 16                              1709                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 16                              1710                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 16                              1711                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 16                              1712                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 16                              1713                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 16                              1714                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 16                              1715                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 16                              1716                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 16                              1717                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 16                              1718                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 16                              1719                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 16                              1720                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 16                              1721                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 16                              1722                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 16                              1723                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 16                              1724                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 16                              1725                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 16                              1726                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 16                              1727                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 16                              1728                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 16                              1729                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 16                              1730                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 16                              1731                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 16                              1732                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 16                              1733                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 16                              1734                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 16                              1735                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 16                              1736                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 16                              1737                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 16                              1738                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 16                              1739                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 16                              1740                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 16                              1741                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 16                              1742                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 16                              1743                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 16                              1744                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 16                              1745                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 16                              1746                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 16                              1747                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 16                              1748                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 16                              1749                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 16                              1750                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 16                              1751                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 16                              1752                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 16                              1753                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 16                              1754                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 16                              1755                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 16                              1756                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 16                              1757                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 16                              1758                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 16                              1759                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 16                              1760                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 16                              1761                                                                             1-Pyr                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               1762                                                                             1-Pyr                                                                              H    H    C O S  H    O  Ete   O  1 1 1                               1763                                                                             1-Pyr                                                                              H    H    C O -- --   -- --    -- 0 0 1                               1764                                                                             1-Pyr                                                                              H    H    C O O  Me   O  --    -- 0 1 1                               1765                                                                             1-Pyr                                                                              H    H    C O O  Me   S  --    -- 0 1 1                               1766                                                                             2-Npe                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               1767                                                                             2-Npe                                                                              H    H    C O S  H    O  Ete   O  1 1 1                               1768                                                                             2-Npe                                                                              H    H    C O -- --   -- --    -- 0 0 1                               1769                                                                             2-Npe                                                                              H    H    C O O  Me   O  --    -- 0 1 1                               1770                                                                             2-Npe                                                                              H    H    C O O  Me   S  --    -- 0 1 1                               1771                                                                             Ph   Ph   H    C O O  H    O  Ete   O  1 1 1                               1772                                                                             Ph   Ph   H    C O S  H    O  Ete   O  1 1 1                               1773                                                                             Ph   Ph   H    C O -- --   -- --    -- 0 0 1                               1774                                                                             Ph   Ph   H    C O O  Me   O  --    -- 0 1 1                               1775                                                                             Ph   Ph   H    C O O  Me   S  --    -- 0 1 1                               1776                                                                             4-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 1                               1777                                                                             4-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 1                               1778                                                                             4-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 1                               1779                                                                             4-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 1                               1780                                                                             4-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 1                               1781                                                                             2-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 1                               1782                                                                             2-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 1                               1783                                                                             2-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 1                               1784                                                                             2-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 1                               1785                                                                             2-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 1                               1786                                                                             Ph   Ph   H    C S O  H    O  Ete   O  1 1 1                               1787                                                                             Ph   Ph   H    C S S  H    O  Ete   O  1 1 1                               1788                                                                             Ph   Ph   H    C S -- --   -- --    -- 0 0 1                               1789                                                                             Ph   Ph   H    C S O  Me   O  --    -- 0 1 1                               1790                                                                             Ph   Ph   H    C S O  Me   S  --    -- 0 1 1                               1791                                                                             Ph   Ph   Ph   C NH                                                                              O  H    O  Ete   O  1 1 1                               1792                                                                             Ph   Ph   Ph   C NH                                                                              S  H    O  Ete   O  1 1 1                               1793                                                                             Ph   Ph   Ph   C NH                                                                              -- --   -- --    -- 0 0 1                               1794                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   O  --    -- 0 1 1                               1795                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   S  --    -- 0 1 1                               1796                                                                             1-Pyr                                                                              H    H    C O O  H    O  Ete   O  1 1 2                               1797                                                                             1-Pyr                                                                              H    H    C O S  H    O  Ete   O  1 1 2                               1798                                                                             1-Pyr                                                                              H    H    C O -- --   -- --    -- 0 0 2                               1799                                                                             1-Pyr                                                                              H    H    C O O  Me   O  --    -- 0 1 2                               1800                                                                             1-Pyr                                                                              H    H    C O O  Me   S  --    -- 0 1 2                               1801                                                                             2-Npe                                                                              H    H    C O O  H    O  Ete   O  1 1 2                               1802                                                                             2-Npe                                                                              H    H    C O S  H    O  Ete   O  1 1 2                               1803                                                                             2-Npe                                                                              H    H    C O -- --   -- --    -- 0 0 2                               1804                                                                             2-Npe                                                                              H    H    C O O  Me   O  --    -- 0 1 2                               1805                                                                             2-Npe                                                                              H    H    C O O  Me   S  --    -- 0 1 2                               1806                                                                             Ph   Ph   H    C O O  H    O  Ete   O  1 1 2                               1807                                                                             Ph   Ph   H    C O S  H    O  Ete   O  1 1 2                               1808                                                                             Ph   Ph   H    C O -- --   -- --    -- 0 0 2                               1809                                                                             Ph   Ph   H    C O O  Me   O  --    -- 0 1 2                               1810                                                                             Ph   Ph   H    C O O  Me   S  --    -- 0 1 2                               1811                                                                             4-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 2                               1812                                                                             4-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 2                               1813                                                                             4-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 2                               1814                                                                             4-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 2                               1815                                                                             4-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 2                               1816                                                                             2-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 2                               1817                                                                             2-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 2                               1818                                                                             2-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 2                               1819                                                                             2-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 2                               1820                                                                             2-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 2                               1821                                                                             Ph   Ph   H    C S O  H    O  Ete   O  1 1 2                               1822                                                                             Ph   Ph   H    C S S  H    O  Ete   O  1 1 2                               1823                                                                             Ph   Ph   H    C S -- --   -- --    -- 0 0 2                               1824                                                                             Ph   Ph   H    C S O  Me   O  --    -- 0 1 2                               1825                                                                             Ph   Ph   H    C S O  Me   S  --    -- 0 1 2                               1826                                                                             Ph   Ph   Ph   C NH                                                                              O  H    O  Ete   O  1 1 2                               1827                                                                             Ph   Ph   Ph   C NH                                                                              S  H    O  Ete   O  1 1 2                               1828                                                                             Ph   Ph   Ph   C NH                                                                              -- --   -- --    -- 0 0 2                               1829                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   O  --    -- 0 1 2                               1830                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   S  --    -- 0 1 2                               1831                                                                             1-Pyr                                                                              H    H    C O O  H    O  Ete   O  1 1 3                               1832                                                                             1-Pyr                                                                              H    H    C O S  H    O  Ete   O  1 1 3                               1833                                                                             1-Pyr                                                                              H    H    C O -- --   -- --    -- 0 0 3                               1834                                                                             1-Pyr                                                                              H    H    C O O  Me   O  --    -- 0 1 3                               1835                                                                             1-Pyr                                                                              H    H    C O O  Me   S  --    -- 0 1 3                               1836                                                                             2-Npe                                                                              H    H    C O O  H    O  Ete   O  1 1 3                               1837                                                                             2-Npe                                                                              H    H    C O S  H    O  Ete   O  1 1 3                               1838                                                                             2-Npe                                                                              H    H    C O -- --   -- --    -- 0 0 3                               1839                                                                             2-Npe                                                                              H    H    C O O  Me   O  --    -- 0 1 3                               1840                                                                             2-Npe                                                                              H    H    C O O  Me   S  --    -- 0 1 3                               1841                                                                             Ph   Ph   H    C O O  H    O  Ete   O  1 1 3                               1842                                                                             Ph   Ph   H    C O S  H    O  Ete   O  1 1 3                               1843                                                                             Ph   Ph   H    C O -- --   -- --    -- 0 0 3                               1844                                                                             Ph   Ph   H    C O O  Me   O  --    -- 0 1 3                               1845                                                                             Ph   Ph   H    C O O  Me   S  --    -- 0 1 3                               1846                                                                             4-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 3                               1847                                                                             4-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 3                               1848                                                                             4-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 3                               1849                                                                             4-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 3                               1850                                                                             4-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 3                               1851                                                                             2-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 3                               1852                                                                             2-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 3                               1853                                                                             2-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 3                               1854                                                                             2-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 3                               1855                                                                             2-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 3                               1856                                                                             Ph   Ph   H    C S O  H    O  Ete   O  1 1 3                               2857                                                                             Ph   Ph   H    C S S  H    O  Ete   O  1 1 3                               1858                                                                             Ph   Ph   H    C S -- --   -- --    -- 0 0 3                               1859                                                                             Ph   Ph   H    C S O  Me   O  --    -- 0 1 3                               1860                                                                             Ph   Ph   H    C S O  Me   S  --    -- 0 1 3                               1861                                                                             Ph   Ph   Ph   C NH                                                                              O  H    O  Ete   O  1 1 3                               1862                                                                             Ph   Ph   Ph   C NH                                                                              S  H    O  Ete   O  1 1 3                               1863                                                                             Ph   Ph   Ph   C NH                                                                              -- --   -- --    -- 0 0 3                               1864                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   O  --    -- 0 1 3                               1865                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   S  --    -- 0 1 3                               1866                                                                             1-Pyr                                                                              H    H    C O O  H    O  Ete   O  1 1 4                               1867                                                                             1-Pyr                                                                              H    H    C O S  H    O  Ete   O  1 1 4                               1868                                                                             1-Pyr                                                                              H    H    C O -- --   -- --    -- 0 0 4                               1869                                                                             1-Pyr                                                                              H    H    C O O  Me   O  --    -- 0 1 4                               1870                                                                             1-Pyr                                                                              H    H    C O O  Me   S  --    -- 0 1 4                               1871                                                                             2-Npe                                                                              H    H    C O O  H    O  Ete   O  1 1 4                               1872                                                                             2-Npe                                                                              H    H    C O S  H    O  Ete   O  1 1 4                               1873                                                                             2-Npe                                                                              H    H    C O -- --   -- --    -- 0 0 4                               1874                                                                             2-Npe                                                                              H    H    C O O  Me   O  --    -- 0 1 4                               1875                                                                             2-Npe                                                                              H    H    C O O  Me   S  --    -- 0 1 4                               1876                                                                             Ph   Ph   H    C O O  H    O  Ete   O  1 1 4                               1877                                                                             Ph   Ph   H    C O S  H    O  Ete   O  1 1 4                               1878                                                                             Ph   Ph   H    C O -- --   -- --    -- 0 0 4                               1879                                                                             Ph   Ph   H    C O O  Me   O  --    -- 0 1 4                               1880                                                                             Ph   Ph   H    C O O  Me   S  --    -- 0 1 4                               1881                                                                             4-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 4                               1882                                                                             4-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 4                               1883                                                                             4-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 4                               1884                                                                             4-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 4                               1885                                                                             4-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 4                               1886                                                                             2-PhPh                                                                             H    H    C O O  H    O  Ete   O  1 1 4                               1887                                                                             2-PhPh                                                                             H    H    C O S  H    O  Ete   O  1 1 4                               1888                                                                             2-PhPh                                                                             H    H    C O -- --   -- --    -- 0 0 4                               1889                                                                             2-PhPh                                                                             H    H    C O O  Me   O  --    -- 0 1 4                               1890                                                                             2-PhPh                                                                             H    H    C O O  Me   S  --    -- 0 1 4                               1891                                                                             Ph   Ph   H    C S O  H    O  Ete   O  1 1 4                               1892                                                                             Ph   Ph   H    C S S  H    O  Ete   O  1 1 4                               1893                                                                             Ph   Ph   H    C S -- --   -- --    -- 0 0 4                               1894                                                                             Ph   Ph   H    C S O  Me   O  --    -- 0 1 4                               1895                                                                             Ph   Ph   H    C S O  Me   S  Ete   -- 0 1 4                               1896                                                                             Ph   Ph   Ph   C NH                                                                              O  H    O  Ete   O  1 1 4                               1897                                                                             Ph   Ph   Ph   C NH                                                                              S  H    O  Ete   O  1 1 4                               1898                                                                             Ph   Ph   Ph   C NH                                                                              -- --   -- --    -- 0 0 4                               1899                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   O  --    -- 0 1 4                               1900                                                                             Ph   Ph   Ph   C NH                                                                              O  Me   S  --    -- 0 1 4                               1901                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 17                              1902                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 17                              1903                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 17                              1904                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 17                              1905                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 17                              1906                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 17                              1907                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 17                              1908                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 17                              1909                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 17                              1910                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 17                              1911                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 17                              1912                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 17                              1913                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 17                              1914                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 17                              1915                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 17                              1916                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 18                              1917                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 18                              1918                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 18                              1919                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 18                              1920                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 18                              1921                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 18                              1922                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 18                              1923                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 18                              1924                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 18                              1925                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 18                              1926                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 18                              1927                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 18                              1928                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 18                              1929                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 18                              1930                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 18                              1931                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 19                              1932                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 19                              1933                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 19                              1934                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 19                              1935                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 19                              1936                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 19                              1937                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 19                              1938                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 19                              1938                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 19                              1940                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 19                              1941                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 19                              1942                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 19                              1943                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 19                              1944                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 19                              1945                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 19                              1946                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 20                              1947                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 20                              1948                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 20                              1949                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 20                              1950                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 20                              1951                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 20                              1952                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 20                              1953                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 20                              1954                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 20                              1955                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 20                              1956                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 20                              1957                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 20                              1958                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 20                              1959                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 20                              1960                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 20                              1961                                                                             3,4-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 1                               1962                                                                             3,4-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 1                               1963                                                                             3,4-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 1                               1964                                                                             3,4-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 1                               1965                                                                             3,4-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 1                               1966                                                                             3,4-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 1                               1967                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 1                               1968                                                                             3,4-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 1                               1969                                                                             3,4-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 1                               1970                                                                             3,4-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 1                               1971                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 1                               1972                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 1                               1973                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 1                               1974                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 1                               1975                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 1                               1976                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 1                               1977                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 1                               1978                                                                             Ph   Ph   Ph   C O NH Me   O  Ete   O  1 1 1                               1979                                                                             Ph   Ph   Ph   C O O  Ph   O  --    -- 0 1 1                               1980                                                                             Ph   Ph   Ph   C O O  4-ClPh                                                                             O  --    -- 0 1 1                               1981                                                                             Ph   Ph   Ph   C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 1                               1982                                                                             Ph   Ph   Ph   C O NH 2-MeOEt                                                                            O  Ete   O  1 1 1                               1983                                                                             Ph   Ph   Ph   C O S  Me   O  --    -- 0 1 1                               1984                                                                             Ph   Ph   Ph   C O S  H    O  --    -- 0 1 1                               1985                                                                             Ph   Ph   Ph   C O O  H    S  Ete   O  1 1 1                               1986                                                                             Ph   Ph   Ph   C O O  Et   O  --    -- 0 1 1                               1987                                                                             Ph   Ph   Ph   C O O  Et   S  --    -- 0 1 1                               1988                                                                             Ph   Ph   Ph   C O O  Bu   O  --    -- 0 1 1                               1989                                                                             Ph   Ph   Ph   C O O  Bu   S  --    -- 0 1 1                               1990                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 1 1                               1991                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 2 1                               1992                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 3 1                               1993                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 4 1                               1994                                                                             Ph   Ph   Ph   C O O  H    O  2-Hpr NH 1 1 1                               1995                                                                             3,5-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 1                               1996                                                                             3,5-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 1                               1997                                                                             3,5-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 1                               1998                                                                             3,5-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 1                               1999                                                                             3,5-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 1                               2000                                                                             3,5-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 1                               2001                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 1                               2002                                                                             3,5-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 1                               2003                                                                             3,5-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 1                               2004                                                                             3,5-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 1                               2005                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 1                               2006                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 1                               2007                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 1                               2008                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 1                               2009                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 1                               2010                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 1                               2011                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 1                               2012                                                                             3,4-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 2                               2013                                                                             3,4-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 2                               2014                                                                             3,4-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 2                               2015                                                                             3,4-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 2                               2016                                                                             3,4-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 2                               2017                                                                             3,4-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 2                               2018                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 2                               2019                                                                             3,4-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 2                               2020                                                                             3,4-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 2                               2021                                                                             3,4-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 2                               2022                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 2                               2023                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 2                               2024                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 2                               2025                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 2                               2026                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 2                               2027                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 2                               2028                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 2                               2029                                                                             Ph   Ph   Ph   C O NH Me   O  Ete   O  1 1 2                               2030                                                                             Ph   Ph   Ph   C O O  Ph   O  --    -- 0 1 2                               2031                                                                             Ph   Ph   Ph   C O O  4-ClPh                                                                             O  --    -- 0 1 2                               2032                                                                             Ph   Ph   Ph   C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 2                               2033                                                                             Ph   Ph   Ph   C O NH 2-MeOEt                                                                            O  Ete   O  1 1 2                               2034                                                                             Ph   Ph   Ph   C O S  Me   O  --    -- 0 1 2                               2035                                                                             Ph   Ph   Ph   C O S  H    O  --    -- 0 1 2                               2036                                                                             Ph   Ph   Ph   C O O  H    S  Ete   O  1 1 2                               2037                                                                             Ph   Ph   Ph   C O O  Et   O  --    -- 0 1 2                               2038                                                                             Ph   Ph   Ph   C O O  Et   S  --    -- 0 1 2                               2039                                                                             Ph   Ph   Ph   C O O  Bu   O  --    -- 0 1 2                               2040                                                                             Ph   Ph   Ph   C O O  Bu   S  --    -- 0 1 2                               2041                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 1 2                               2042                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 2 2                               2043                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 3 2                               2044                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 4 2                               2045                                                                             Ph   Ph   Ph   C O O  H    O  2-Hpr NH 1 1 2                               2046                                                                             3,5-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 2                               2047                                                                             3,5-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 2                               2048                                                                             3,5-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 2                               2049                                                                             3,5-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 2                               2050                                                                             3,5-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 2                               2051                                                                             3,5-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 2                               2052                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 2                               2053                                                                             3,5-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 2                               2054                                                                             3,5-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 2                               2055                                                                             3,5-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 2                               2056                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 2                               2057                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 2                               2058                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 2                               2059                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 2                               2060                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 2                               2061                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 2                               2062                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 2                               2063                                                                             3,4-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 3                               2064                                                                             3,4-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 3                               2065                                                                             3,4-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 3                               2066                                                                             3,4-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 3                               2067                                                                             3,4-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 3                               2068                                                                             3,4-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 3                               2069                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 3                               2070                                                                             3,4-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 3                               2071                                                                             3,4-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 3                               2072                                                                             3,4-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 3                               2073                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 3                               2074                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 3                               2075                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 3                               2076                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 3                               2077                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 3                               2078                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 3                               2079                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 3                               2080                                                                             Ph   Ph   Ph   C O NH Me   O  Ete   O  1 1 3                               2081                                                                             Ph   Ph   Ph   C O O  Ph   O  --    -- 0 1 3                               2082                                                                             Ph   Ph   Ph   C O O  4-ClPh                                                                             O  --    -- 0 1 3                               2083                                                                             Ph   Ph   Ph   C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 3                               2084                                                                             Ph   Ph   Ph   C O NH 2-MeOEt                                                                            O  Ete   O  1 1 3                               2085                                                                             Ph   Ph   Ph   C O S  Me   O  --    -- 0 1 3                               2086                                                                             Ph   Ph   Ph   C O S  H    O  --    -- 0 1 3                               2087                                                                             Ph   Ph   Ph   C O O  H    S  Ete   O  1 1 3                               2088                                                                             Ph   Ph   Ph   C O O  Et   O  --    -- 0 1 3                               2089                                                                             Ph   Ph   Ph   C O O  Et   S  --    -- 0 1 3                               2090                                                                             Ph   Ph   Ph   C O O  Bu   O  --    -- 0 1 3                               2091                                                                             Ph   Ph   Ph   C O O  Bu   S  --    -- 0 1 3                               2092                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 1 3                               2093                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 2 3                               2094                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 3 3                               2095                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 4 3                               2096                                                                             Ph   Ph   Ph   C O O  H    O  2-Hpr NH 1 1 3                               2097                                                                             3,5-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 3                               2098                                                                             3,5-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 3                               2099                                                                             3,5-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 3                               2100                                                                             3,5-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 3                               2101                                                                             3,5-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 3                               2102                                                                             3,5-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 3                               2103                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 3                               2104                                                                             3,5-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 3                               2105                                                                             3,5-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 3                               2106                                                                             3,5-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 3                               2107                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 3                               2108                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 3                               2109                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 3                               2110                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 3                               2111                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 3                               2112                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 3                               2113                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 3                               2114                                                                             3,4-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 4                               2115                                                                             3,4-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 4                               2116                                                                             3,4-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 4                               2117                                                                             3,4-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 4                               2118                                                                             3,4-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 4                               2119                                                                             3,4-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 4                               2120                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 4                               2121                                                                             3,4-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 4                               2122                                                                             3,4-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 4                               2123                                                                             3,4-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 4                               2124                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 4                               2125                                                                             3,4-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 4                               2126                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 4                               2127                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 4                               2128                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 4                               2129                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 4                               2130                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 4                               2131                                                                             Ph   Ph   Ph   C O NH Me   O  Ete   O  1 1 4                               2132                                                                             Ph   Ph   Ph   C O O  Ph   O  --    -- 0 1 4                               2133                                                                             Ph   Ph   Ph   C O O  4-ClPh                                                                             O  --    -- 0 1 4                               2134                                                                             Ph   Ph   Ph   C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 4                               2135                                                                             Ph   Ph   Ph   C O NH 2-MeOEt                                                                            O  Ete   O  1 1 4                               2136                                                                             Ph   Ph   Ph   C O S  Me   O  --    -- 0 1 4                               2137                                                                             Ph   Ph   Ph   C O S  H    O  --    -- 0 1 4                               2138                                                                             Ph   Ph   Ph   C O O  H    S  Ete   O  1 1 4                               2139                                                                             Ph   Ph   Ph   C O O  Et   O  --    -- 0 1 4                               2140                                                                             Ph   Ph   Ph   C O O  Et   S  --    -- 0 1 4                               2141                                                                             Ph   Ph   Ph   C O O  Bu   O  --    -- 0 1 4                               2142                                                                             Ph   Ph   Ph   C O O  Bu   S  --    -- 0 1 4                               2143                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 1 4                               2144                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 2 4                               2145                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 3 4                               2146                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  6 4 4                               2147                                                                             Ph   Ph   Ph   C O O  H    O  2-Hpr NH 1 1 4                               2148                                                                             3,5-Dbp                                                                            H    H    C O NH Me   O  Ete   O  1 1 4                               2149                                                                             3,5-Dbp                                                                            H    H    C O O  Ph   O  --    -- 0 1 4                               2150                                                                             3,5-Dbp                                                                            H    H    C O O  4-ClPh                                                                             O  --    -- 0 1 4                               2151                                                                             3,5-Dbp                                                                            H    H    C O NH 2-NH.sub.2 Et                                                                      O  Ete   O  1 1 4                               2152                                                                             3,5-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Ete   O  1 1 4                               2153                                                                             3,5-Dbp                                                                            H    H    C O S  Me   O  --    -- 0 1 4                               2154                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  --    -- 0 1 4                               2155                                                                             3,5-Dbp                                                                            H    H    C O O  H    S  Ete   O  1 1 4                               2156                                                                             3,5-Dbp                                                                            H    H    C O O  Et   O  --    -- 0 1 4                               2157                                                                             3,5-Dbp                                                                            H    H    C O O  Et   S  --    -- 0 1 4                               2158                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   O  --    -- 0 1 4                               2159                                                                             3,5-Dbp                                                                            H    H    C O O  Bu   S  --    -- 0 1 4                               2160                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 1 4                               2161                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 2 4                               2162                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 3 4                               2163                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  6 4 4                               2164                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  2-Hpr NH 1 1 4                               2165                                                                             4-MePh                                                                             Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2166                                                                             4-MePh                                                                             4-MePh                                                                             Ph   C O O  H    O  Ete   O  1 1 1                               2167                                                                             4-MePh                                                                             4-MePh                                                                             4-MePh                                                                             C O O  H    O  Ete   O  1 1 1                               2168                                                                             4-tBuPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2169                                                                             4-tBuPh                                                                            4-tBuPh                                                                            Ph   C O O  H    O  Ete   O  1 1 1                               2170                                                                             4-tBuPh                                                                            4-tBuPh                                                                            4-tBuPh                                                                            C O O  H    O  Ete   O  1 1 1                               2171                                                                             4-NO2Ph                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2172                                                                             4-NO2Ph                                                                            4-NO2Ph                                                                            Ph   C O O  H    O  Ete   O  1 1 1                               2173                                                                             4-FPh                                                                              Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2174                                                                             4-FPh                                                                              4-FPh                                                                              Ph   C O O  H    O  Ete   O  1 1 1                               2175                                                                             2,4-diFPh                                                                          Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2176                                                                             2-ClPh                                                                             Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2177                                                                             4-ClPh                                                                             Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2178                                                                             4-ClPh                                                                             4-ClPh                                                                             Ph   C O O  H    O  Ete   O  1 1 1                               2179                                                                             4-BrPh                                                                             Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2180                                                                             4-BrPh                                                                             4-BrPh                                                                             Ph   C O O  H    O  Ete   O  1 1 1                               2181                                                                             4-IPh                                                                              Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2182                                                                             4-tBuOPh                                                                           Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2183                                                                             4-EtOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2184                                                                             4-EtOPh                                                                            4-EtOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 1                               2185                                                                             2-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 1                               2186                                                                             4-BzOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 1                               2187                                                                             4-BzOPh                                                                            4-BzOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 1                               2188                                                                             4-MeOPh                                                                            4-MeOPh                                                                            4-MeOPh                                                                            C O O  H    O  Ete   O  1 1 1                               2189                                                                             9-Ant                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               2190                                                                             2-Ant                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               2191                                                                             1-Npe                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               2192                                                                             3-PhOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 1                               2193                                                                             4-PhOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 1                               2194                                                                             2-Anq                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               2195                                                                             4-Pha                                                                              H    H    C O O  H    O  Ete   O  1 1 1                               2196                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  6 1 1                               2197                                                                             3,4-Dbp                                                                            H    H    C O NH Et   O  Ete   O  6 1 1                               2198                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  6 1 1                               2199                                                                             3,4-Dbp                                                                            H    H    C O NH 2-NH2Et                                                                            O  Ete   O  6 1 1                               2200                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  2 1 1                               2201                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  2 1 1                               2202                                                                             3,4-Dbp                                                                            H    H    C O O  2-NO2Ph                                                                            O  --    -- 0 1 1                               2203                                                                             3,4-Dbp                                                                            H    H    C O O  4-NO2Ph                                                                            O  --    -- 0 1 1                               2204                                                                             3,4-Dbp                                                                            H    H    C O O  2-FPh                                                                              O  --    -- 0 1 1                               2205                                                                             3,4-Dbp                                                                            H    H    C O O  2-BrPh                                                                             O  --    -- 0 1 1                               2206                                                                             3,4-Dbp                                                                            H    H    C O O  2-IPh                                                                              O  --    -- 0 1 1                               2207                                                                             3,4-Dbp                                                                            H    H    C O O  4-MeOPh                                                                            O  --    -- 0 1 1                               2208                                                                             3,4-Dbp                                                                            H    H    C O O  4-MeSPh                                                                            O  --    -- 0 1 1                               2209                                                                             3,4-Dbp                                                                            H    H    C O O  4-EtOPh                                                                            O  --    -- 0 1 1                               2210                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Trim  O  1 1 1                               2211                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Tetm  O  1 1 1                               2212                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Pnm   O  1 1 1                               2213                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Hexm  O  1 1 1                               2214                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Hepm  O  1 1 1                               2215                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Octm  O  1 1 1                               2216                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Nonm  O  1 1 1                               2217                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Decm  O  1 1 1                               2218                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Pre   O  1 1 1                               2219                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  1-Me-Trim                                                                           O  1 1 1                               2220                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  2-Me-Tetm                                                                           O  1 1 1                               2221                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Trim  O  1 1 1                               2222                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Tetm  O  1 1 1                               2223                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Penm  O  1 1 1                               2224                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Hexm  O  1 1 1                               2225                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Hepm  O  1 1 1                               2226                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Octm  O  1 1 1                               2227                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Nonm  O  1 1 1                               2228                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Decm  O  1 1 1                               2229                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Pre   O  1 1 1                               2230                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  1-Me-Trim                                                                           O  1 1 1                               2231                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  2-Me-Tetm                                                                           O  1 1 1                               2232                                                                             3,4-Dbp                                                                            H    H    C O NH Ph   O  Ete   O  1 1 1                               2233                                                                             3,4-Dbp                                                                            H    H    C O NH 2-ClPh                                                                             O  Ete   O  1 1 1                               2234                                                                             3,4-Dbp                                                                            H    H    C O NH Me   O  Trim  O  1 1 1                               2235                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Trim  O  1 1 1                               2236                                                                             3,4-Dbp                                                                            H    H    C O NH 2-NH2Et                                                                            O  Trim  O  1 1 1                               2237                                                                             3,4-Dbp                                                                            H    H    C O NH 2-MeOEt                                                                            O  Trim  O  1 1 1                               2238                                                                             3,4-Dbp                                                                            H    H    C O NH Ph   O  Trim  O  1 1 1                               2239                                                                             3,4-Dbp                                                                            H    H    C O NH 2-ClPh                                                                             O  Trim  O  1 1 1                               2240                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Tetm  O  1 1 1                               2241                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Penm  O  1 1 1                               2242                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Hexm  O  1 1 1                               2243                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Hepm  O  1 1 1                               2244                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Octm  O  1 1 1                               2245                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Nonm  O  1 1 1                               2246                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Decm  O  1 1 1                               2247                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Pre   O  1 1 1                               2248                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  1-Me-Trim                                                                           O  1 1 1                               2249                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  2-Me-Tetm                                                                           O  1 1 1                               2250                                                                             Ph   Ph   Ph   C NH                                                                              O  H    O  Ete   O  6 1 1                               2251                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 21                              2252                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 21                              2253                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 21                              2254                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 21                              2255                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 21                              2256                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 21                              2257                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 21                              2258                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 21                              2259                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 21                              2260                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 21                              2261                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 21                              2262                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 21                              2263                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 21                              2264                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 21                              2265                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 21                              2266                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 22                              2267                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 22                              2268                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 22                              2269                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 22                              2270                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 22                              2271                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 22                              2272                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 22                              2273                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 22                              2274                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 22                              2275                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 22                              2276                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 22                              2277                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 22                              2278                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 22                              2279                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 22                              2280                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 22                              2281                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 23                              2282                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 23                              2283                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 23                              2284                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 23                              2285                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 23                              2286                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 23                              2287                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 23                              2288                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 23                              2289                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 23                              2290                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 23                              2291                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 23                              2292                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 23                              2293                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 23                              2294                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 23                              2295                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 23                              2296                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 24                              2297                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 24                              2298                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 24                              2299                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 24                              2300                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 24                              2301                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 24                              2302                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 24                              2303                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 24                              2304                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 24                              2305                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 24                              2306                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 24                              2307                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 24                              2308                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 24                              2309                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 24                              2310                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 24                              2311                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 25                              2312                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 25                              2313                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 25                              2314                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 25                              2315                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 25                              2316                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 25                              2317                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 25                              2318                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 25                              2319                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 25                              2320                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 25                              2321                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 25                              2322                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 25                              2323                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 25                              2324                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 25                              2325                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 25                              2326                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 17                              2327                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 18                              2328                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 19                              2329                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 20                              2330                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 21                              2331                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 22                              2332                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 23                              2333                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 24                              2334                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 25                              2335                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 26                              2336                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 26                              2337                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 26                              2338                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 26                              2339                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 26                              2340                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 26                              2341                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 26                              2342                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 26                              2343                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 26                              2344                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 26                              2345                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 26                              2346                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 26                              2347                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 26                              2348                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 26                              2349                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 26                              2350                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 26                              2351                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 26                              2352                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 26                              2353                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 26                              2354                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 26                              2355                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 26                              2356                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 26                              2357                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 26                              2358                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 26                              2359                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 26                              2360                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 26                              2361                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 26                              2362                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 26                              2363                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 26                              2364                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 26                              2365                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 26                              2366                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 26                              2367                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 26                              2368                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 26                              2369                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 26                              2370                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 26                              2371                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 26                              2372                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 26                              2373                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 26                              2374                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 26                              2375                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 26                              2376                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 26                              2377                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 26                              2378                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 26                              2379                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 26                              2380                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 26                              2381                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 26                              2382                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 26                              2383                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 26                              2384                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 26                              2385                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 26                              2386                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 26                              2387                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 26                              2388                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 26                              2389                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 26                              2390                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 26                              2391                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 26                              2392                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 26                              2393                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 26                              2394                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 26                              2395                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 26                              2396                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 26                              2397                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 26                              2398                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 26                              2399                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 26                              2400                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 26                              2401                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 26                              2402                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 26                              2403                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 26                              2404                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 26                              2405                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 26                              2406                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 26                              2407                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 26                              2408                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 26                              2409                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 26                              2410                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 26                              2411                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 26                              2412                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 26                              2413                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 26                              2414                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 26                              2415                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 26                              2416                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 26                              2417                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 26                              2418                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 26                              2419                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 26                              2420                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 26                              2421                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 26                              2422                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 26                              2423                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 26                              2424                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 26                              2425                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 26                              2426                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 26                              2427                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 26                              2428                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 26                              2429                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 26                              2430                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 26                              2431                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 26                              2432                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 26                              2433                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 26                              2434                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 26                              2435                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 26                              2436                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 26                              2437                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 26                              2438                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 26                              2439                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 26                              2440                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 26                              2441                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 26                              2442                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 26                              2443                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 26                              2444                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 26                              2445                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 27                              2446                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 27                              2447                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 27                              2448                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 27                              2449                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 27                              2450                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 27                              2451                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 27                              2452                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 27                              2453                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 27                              2454                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 27                              2455                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 27                              2456                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 27                              2457                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 27                              2458                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 27                              2459                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 27                              2460                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 27                              2461                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 27                              2462                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 27                              2463                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 27                              2464                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 27                              2465                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 27                              2466                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 27                              2467                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 27                              2468                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 27                              2469                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 27                              2470                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 27                              2471                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 27                              2472                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 27                              2473                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 27                              2474                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 27                              2475                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 27                              2476                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 27                              2477                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 27                              2478                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 27                              2479                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 27                              2480                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 27                              2481                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 27                              2482                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 27                              2483                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 27                              2482                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 27                              2485                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 27                              2486                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 27                              2487                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 27                              2488                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 27                              2489                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 27                              2490                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 27                              2491                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 27                              2492                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 27                              2493                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 27                              2494                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 27                              2495                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 27                              2496                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 27                              2497                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 27                              2498                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 27                              2499                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 27                              2500                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 27                              2501                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 27                              2502                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 27                              2503                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 27                              2504                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 27                              2505                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 27                              2506                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 27                              2507                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 27                              2508                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 27                              2509                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 27                              2510                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 27                              2511                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 27                              2512                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 27                              2513                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 27                              2514                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 27                              2515                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 27                              2516                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 27                              2517                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 27                              2518                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 27                              2519                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 27                              2520                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 27                              2521                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 27                              2522                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 27                              2523                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 27                              2524                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 27                              2525                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 27                              2526                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 27                              2527                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 27                              2528                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 27                              2529                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 27                              2530                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 27                              2531                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 27                              2532                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 27                              2533                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 27                              2534                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 27                              2535                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 27                              2536                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 27                              2537                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 27                              2538                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 27                              2539                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 27                              2540                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 27                              2541                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 27                              2542                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 27                              2543                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 27                              2544                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 27                              2545                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 27                              2546                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 27                              2547                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 27                              2548                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 27                              2549                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 27                              2550                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 27                              2551                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 27                              2552                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 27                              2553                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 27                              2554                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 27                              2555                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 28                              2556                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 28                              2557                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 28                              2558                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 28                              2559                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 28                              2560                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 28                              2561                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 28                              2562                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 28                              2563                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 28                              2564                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 28                              2565                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 28                              2566                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 28                              2567                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 28                              2568                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 28                              2569                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 28                              2570                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 28                              2571                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 28                              2572                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 28                              2573                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 28                              2574                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 28                              2575                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 28                              2576                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 28                              2577                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 28                              2578                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 28                              2579                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 28                              2580                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 28                              2581                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 28                              2582                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 28                              2583                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 28                              2584                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 28                              2585                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 28                              2586                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 28                              2587                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 28                              2588                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 28                              2589                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 28                              2590                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 28                              2591                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 28                              2592                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 28                              2593                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 28                              2594                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 28                              2595                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 28                              2596                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 28                              2597                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 28                              2598                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 28                              2599                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 28                              2600                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 28                              2601                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 28                              2602                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 28                              2603                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 28                              2604                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 28                              2605                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 28                              2606                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 28                              2607                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 28                              2608                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 28                              2609                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 28                              2610                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 28                              2611                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 28                              2612                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 28                              2613                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 28                              2614                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 28                              2615                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 28                              2616                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 28                              2617                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 28                              2618                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 28                              2619                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 28                              2620                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 28                              2621                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 28                              2622                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 28                              2623                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 28                              2624                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 28                              2625                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 28                              2626                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 28                              2627                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 28                              2628                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 28                              2629                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 28                              2630                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 28                              2631                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 28                              2632                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 28                              2633                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 28                              2634                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 28                              2635                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 28                              2636                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 28                              2637                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 28                              2638                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 28                              2639                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 28                              2640                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 28                              2641                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 28                              2642                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 28                              2643                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 28                              2644                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 28                              2645                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 28                              2646                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 28                              2647                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 28                              2648                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 28                              2649                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 28                              2650                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 28                              2651                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 28                              2652                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 28                              2653                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 28                              2654                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 28                              2655                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 28                              2656                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 28                              2657                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 28                              2658                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 28                              2659                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 28                              2660                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 28                              2661                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 28                              2662                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 28                              2663                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 28                              2664                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 28                              2665                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 29                              2666                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 29                              2667                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 29                              2668                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 29                              2669                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 29                              2670                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 29                              2671                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 29                              2672                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 29                              2673                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 29                              2674                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 29                              2675                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 29                              2676                                                                             Ph   Ph   Ph   C O O  H    O  Ete   O  1 1 29                              2677                                                                             Ph   Ph   Ph   C O S  H    O  Ete   O  1 1 29                              2678                                                                             Ph   Ph   Ph   C O -- --   -- --    -- 0 0 29                              2679                                                                             Ph   Ph   Ph   C O O  Me   O  --    -- 0 1 29                              2680                                                                             Ph   Ph   Ph   C O O  Me   S  --    -- 0 1 29                              2681                                                                             Ph   Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 29                              2682                                                                             Ph   Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 29                              2683                                                                             Ph   Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 29                              2684                                                                             Ph   Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 29                              2685                                                                             Ph   Ph   Ph   C O NH Pr   O  Ete   O  1 1 29                              2686                                                                             Ph   Ph   Ph   C O O  Me   NH Trim  -- 1 1 29                              2687                                                                             3,5-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 29                              2688                                                                             3,5-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 29                              2689                                                                             3,5-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 29                              2690                                                                             3,5-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 29                              2691                                                                             3,5-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 29                              2692                                                                             3,5-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 29                              2693                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 29                              2694                                                                             3,5-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 29                              2695                                                                             3,5-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 29                              2696                                                                             3,5-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 29                              2697                                                                             3,5-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 29                              2698                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  H    O  Ete   O  1 1 29                              2699                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O S  H    O  Ete   O  1 1 29                              2700                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O -- --   -- --    -- 0 0 29                              2701                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   O  --    -- 0 1 29                              2702                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   S  --    -- 0 1 29                              2703                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 29                              2704                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    O  --    -- 0 1 29                              2705                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Mee                                                                              H    S  --    -- 0 1 29                              2706                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O Phe                                                                              H    O  --    -- 0 1 29                              2707                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O NH Pr   O  Ete   O  1 1 29                              2708                                                                             4-MeOPh                                                                            4-MeOPh                                                                            Ph   C O O  Me   NH Trim  -- 1 1 29                              2709                                                                             4-MeOPh                                                                            Ph   Ph   C O O  H    O  Ete   O  1 1 29                              2710                                                                             4-MeOPh                                                                            Ph   Ph   C O S  H    O  Ete   O  1 1 29                              2711                                                                             4-MeOPh                                                                            Ph   Ph   C O -- --   -- --    -- 0 0 29                              2712                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   O  --    -- 0 1 29                              2713                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   S  --    -- 0 1 29                              2714                                                                             4-MeOPh                                                                            Ph   Ph   C O O  2-ClPh                                                                             O  --    -- 0 1 29                              2715                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    O  --    -- 0 1 29                              2716                                                                             4-MeOPh                                                                            Ph   Ph   C O Mee                                                                              H    S  --    -- 0 1 29                              2717                                                                             4-MeOPh                                                                            Ph   Ph   C O Phe                                                                              H    O  --    -- 0 1 29                              2718                                                                             4-MeOPh                                                                            Ph   Ph   C O NH Pr   O  Ete   O  1 1 29                              2719                                                                             4-MeOPh                                                                            Ph   Ph   C O O  Me   NH Trim  -- 1 1 29                              2720                                                                             tBu  Ph   Ph   Si                                                                              O O  H    O  Ete   O  1 1 29                              2721                                                                             tBu  Ph   Ph   Si                                                                              O S  H    O  Ete   O  1 1 29                              2722                                                                             tBu  Ph   Ph   Si                                                                              O -- --   -- --    -- 0 0 29                              2723                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   O  --    -- 0 1 29                              2724                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   S  --    -- 0 1 29                              2725                                                                             tBu  Ph   Ph   Si                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 29                              2726                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    O  --    -- 0 1 29                              2727                                                                             tBu  Ph   Ph   Si                                                                              O Mee                                                                              H    S  --    -- 0 1 29                              2728                                                                             tBu  Ph   Ph   Si                                                                              O Phe                                                                              H    O  --    -- 0 1 29                              2729                                                                             tBu  Ph   Ph   Si                                                                              O NH Pr   O  Ete   O  1 1 29                              2730                                                                             tBu  Ph   Ph   Si                                                                              O O  Me   NH Trim  -- 1 1 29                              2731                                                                             Ph   Ph   Ph   C S O  H    O  Ete   O  1 1 29                              2732                                                                             Ph   Ph   Ph   C S S  H    O  Ete   O  1 1 29                              2733                                                                             Ph   Ph   Ph   C S -- --   -- --    -- 0 0 29                              2734                                                                             Ph   Ph   Ph   C S O  Me   O  --    -- 0 1 29                              2735                                                                             Ph   Ph   Ph   C S O  Me   S  --    -- 0 1 29                              2736                                                                             Ph   Ph   Ph   C S O  2-ClPh                                                                             O  --    -- 0 1 29                              2737                                                                             Ph   Ph   Ph   C S Mee                                                                              H    O  --    -- 0 1 29                              2738                                                                             Ph   Ph   Ph   C S Mee                                                                              H    S  --    -- 0 1 29                              2739                                                                             Ph   Ph   Ph   C S Phe                                                                              H    O  --    -- 0 1 29                              2740                                                                             Ph   Ph   Ph   C S NH Pr   O  Ete   O  1 1 29                              2741                                                                             Ph   Ph   Ph   C S O  Me   NH Trim  -- 1 1 29                              2742                                                                             4-BzOPh                                                                            H    H    C O O  H    O  Ete   O  1 1 29                              2743                                                                             4-BzOPh                                                                            H    H    C O S  H    O  Ete   O  1 1 29                              2744                                                                             4-BzOPh                                                                            H    H    C O -- --   -- --    -- 0 0 29                              2745                                                                             4-BzOPh                                                                            H    H    C O O  Me   O  --    -- 0 1 29                              2746                                                                             4-BzOPh                                                                            H    H    C O O  Me   S  --    -- 0 1 29                              2747                                                                             4-BzOPh                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 29                              2748                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 29                              2749                                                                             4-BzOPh                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 29                              2750                                                                             4-BzOPh                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 29                              2751                                                                             4-BzOPh                                                                            H    H    C O NH Pr   O  Ete   O  1 1 29                              2752                                                                             4-BzOPh                                                                            H    H    C O O  Me   NH Trim  -- 1 1 29                              2753                                                                             Ph   Xanthen-9-yl                                                                              O O  H    O  Ete   O  1 1 29                              2754                                                                             Ph   Xanthen-9-yl                                                                              O S  H    O  Ete   O  1 1 29                              2755                                                                             Ph   Xanthen-9-yl                                                                              O -- --   -- --    -- 0 0 29                              2756                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   O  --    -- 0 1 29                              2757                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   S  --    -- 0 1 29                              2758                                                                             Ph   Xanthen-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 29                              2759                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 29                              2760                                                                             Ph   Xanthen-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 29                              2761                                                                             Ph   Xanthen-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 29                              2762                                                                             Ph   Xanthen-9-yl                                                                              O NH Pr   O  Ete   O  1 1 29                              2763                                                                             Ph   Xanthen-9-yl                                                                              O O  Me   NH Trim  -- 1 1 29                              2764                                                                             Ph   Fluoren-9-yl                                                                              O O  H    O  Ete   O  1 1 29                              2765                                                                             Ph   Fluoren-9-yl                                                                              O S  H    O  Ete   O  1 1 29                              2766                                                                             Ph   Fluoren-9-yl                                                                              O -- --   -- --    -- 0 0 29                              2767                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   O  --    -- 0 1 29                              2768                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   S  --    -- 0 1 29                              2769                                                                             Ph   Fluoren-9-yl                                                                              O O  2-ClPh                                                                             O  --    -- 0 1 29                              2770                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    O  --    -- 0 1 29                              2771                                                                             Ph   Fluoren-9-yl                                                                              O Mee                                                                              H    S  --    -- 0 1 29                              2772                                                                             Ph   Fluoren-9-yl                                                                              O Phe                                                                              H    O  --    -- 0 1 29                              2773                                                                             Ph   Fluoren-9-yl                                                                              O NH Pr   O  Ete   O  1 1 29                              2774                                                                             Ph   Fluoren-9-yl                                                                              O O  Me   NH Trim  -- 1 1 29                              2775                                                                             3,4-Dbp                                                                            H    H    C S O  H    O  Ete   O  1 1 1                               2776                                                                             3,4-Dbp                                                                            H    H    C S S  H    O  Ete   O  1 1 1                               2777                                                                             3,4-Dbp                                                                            H    H    C S -- --   -- --    -- 0 0 1                               2778                                                                             3,4-Dbp                                                                            H    H    C S O  Me   O  --    -- 0 1 1                               2779                                                                             3,4-Dbp                                                                            H    H    C S O  Me   S  --    -- 0 1 1                               2780                                                                             3,4-Dbp                                                                            H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 1                               2781                                                                             3,4-Dbp                                                                            H    H    C S Mee                                                                              H    O  --    -- 0 1 1                               2782                                                                             3,4-Dbp                                                                            H    H    C S Mee                                                                              H    S  --    -- 0 1 1                               2783                                                                             3,4-Dbp                                                                            H    H    C S Phe                                                                              H    O  --    -- 0 1 1                               2784                                                                             3,4-Dbp                                                                            H    H    C S NH Pr   O  Ete   O  1 1 1                               2785                                                                             3,4-Dbp                                                                            H    H    C S O  Me   NH Trim  -- 1 1 1                               2786                                                                             9-Ant                                                                              H    H    C S O  H    O  Ete   O  1 1 1                               2787                                                                             9-Ant                                                                              H    H    C S S  H    O  Ete   O  1 1 1                               2788                                                                             9-Ant                                                                              H    H    C S -- --   -- --    -- 0 0 1                               2789                                                                             9-Ant                                                                              H    H    C S O  Me   O  --    -- 0 1 1                               2790                                                                             9-Ant                                                                              H    H    C S O  Me   S  --    -- 0 1 1                               2791                                                                             9-Ant                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 1                               2792                                                                             9-Ant                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 1                               2793                                                                             9-Ant                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 1                               2794                                                                             9-Ant                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 1                               2795                                                                             9-Ant                                                                              H    H    C S NH Pr   O  Ete   O  1 1 1                               2796                                                                             9-Ant                                                                              H    H    C S O  Me   NH Trim  -- 1 1 1                               2797                                                                             2-Npe                                                                              H    H    C S O  H    O  Ete   O  1 1 1                               2798                                                                             2-Npe                                                                              H    H    C S S  H    O  Ete   O  1 1 1                               2799                                                                             2-Npe                                                                              H    H    C S -- --   -- --    -- 0 0 1                               2800                                                                             2-Npe                                                                              H    H    C S O  Me   O  --    -- 0 1 1                               2801                                                                             2-Npe                                                                              H    H    C S O  Me   S  --    -- 0 1 1                               2802                                                                             2-Npe                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 1                               2803                                                                             2-Npe                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 1                               2804                                                                             2-Npe                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 1                               2805                                                                             2-Npe                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 1                               2806                                                                             2-Npe                                                                              H    H    C S NH Pr   O  Ete   O  1 1 1                               2807                                                                             2-Npe                                                                              H    H    C S O  Me   NH Trim  -- 1 1 1                               2808                                                                             Bdbbp                                                                              H    H    C S O  H    O  Ete   O  1 1 1                               2809                                                                             Bdbbp                                                                              H    H    C S S  H    O  Ete   O  1 1 1                               2810                                                                             Bdbbp                                                                              H    H    C S -- --   -- --    -- 0 0 1                               2811                                                                             Bdbbp                                                                              H    H    C S O  Me   O  --    -- 0 1 1                               2812                                                                             Bdbbp                                                                              H    H    C S O  Me   S  --    -- 0 1 1                               2813                                                                             Bdbbp                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 1                               2814                                                                             Bdbbp                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 1                               2815                                                                             Bdbbp                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 1                               2816                                                                             Bdbbp                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 1                               2817                                                                             Bdbbp                                                                              H    H    C S NH Pr   O  Ete   O  1 1 1                               2818                                                                             Bdbbp                                                                              H    H    C S O  Me   NH Trim  -- 1 1 1                               2819                                                                             3,4-Dbp                                                                            H    H    C S O  H    O  Ete   O  1 1 28                              2820                                                                             3,4-Dbp                                                                            H    H    C S S  H    O  Ete   O  1 1 28                              2821                                                                             3,4-Dbp                                                                            H    H    C S -- --   -- --    -- 0 0 28                              2822                                                                             3,4-Dbp                                                                            H    H    C S O  Me   O  --    -- 0 1 28                              2823                                                                             3,4-Dbp                                                                            H    H    C S O  Me   S  --    -- 0 1 28                              2824                                                                             3,4-Dbp                                                                            H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 28                              2825                                                                             3,4-Dbp                                                                            H    H    C S Mee                                                                              H    O  --    -- 0 1 28                              2826                                                                             3,4-Dbp                                                                            H    H    C S Mee                                                                              H    S  --    -- 0 1 28                              2827                                                                             3,4-Dbp                                                                            H    H    C S Phe                                                                              H    O  --    -- 0 1 28                              2828                                                                             3,4-Dbp                                                                            H    H    C S NH Pr   O  Ete   O  1 1 28                              2829                                                                             3,4-Dbp                                                                            H    H    C S O  Me   NH Trim  -- 1 1 28                              2830                                                                             9-Ant                                                                              H    H    C S O  H    O  Ete   O  1 1 28                              2831                                                                             9-Ant                                                                              H    H    C S S  H    O  Ete   O  1 1 28                              2832                                                                             9-Ant                                                                              H    H    C S -- --   -- --    -- 0 0 28                              2833                                                                             9-Ant                                                                              H    H    C S O  Me   O  --    -- 0 1 28                              2834                                                                             9-Ant                                                                              H    H    C S O  Me   S  --    -- 0 1 28                              2835                                                                             9-Ant                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 28                              2836                                                                             9-Ant                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 28                              2837                                                                             9-Ant                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 28                              2838                                                                             9-Ant                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 28                              2839                                                                             9-Ant                                                                              H    H    C S NH Pr   O  Ete   O  1 1 28                              2840                                                                             9-Ant                                                                              H    H    C S O  Me   NH Trim  -- 1 1 28                              2841                                                                             2-Npe                                                                              H    H    C S O  H    O  Ete   O  1 1 28                              2842                                                                             2-Npe                                                                              H    H    C S S  H    O  Ete   O  1 1 28                              2843                                                                             2-Npe                                                                              H    H    C S -- --   -- --    -- 0 0 28                              2844                                                                             2-Npe                                                                              H    H    C S O  Me   O  --    -- 0 1 28                              2845                                                                             2-Npe                                                                              H    H    C S O  Me   S  --    -- 0 1 28                              2846                                                                             2-Npe                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 28                              2847                                                                             2-Npe                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 28                              2848                                                                             2-Npe                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 28                              2849                                                                             2-Npe                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 28                              2850                                                                             2-Npe                                                                              H    H    C S NH Pr   O  Ete   O  1 1 28                              2851                                                                             2-Npe                                                                              H    H    C S O  Me   NH Trim  -- 1 1 28                              2852                                                                             Bdbbp                                                                              H    H    C S O  H    O  Ete   O  1 1 28                              2853                                                                             Bdbbp                                                                              H    H    C S S  H    O  Ete   O  1 1 28                              2854                                                                             Bdbbp                                                                              H    H    C S -- --   -- --    -- 0 0 28                              2855                                                                             Bdbbp                                                                              H    H    C S O  Me   O  --    -- 0 1 28                              2856                                                                             Bdbbp                                                                              H    H    C S O  Me   S  --    -- 0 1 28                              2857                                                                             Bdbbp                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 28                              2858                                                                             Bdbbp                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 28                              2859                                                                             Bdbbp                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 28                              2860                                                                             Bdbbp                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 28                              2861                                                                             Bdbbp                                                                              H    H    C S NH Pr   O  Ete   O  1 1 28                              2862                                                                             Bdbbp                                                                              H    H    C S O  Me   NH Trim  -- 1 1 28                              2863                                                                             3,4-Dbp                                                                            H    H    C S O  H    O  Ete   O  1 1 29                              2864                                                                             3,4-Dbp                                                                            H    H    C S S  H    O  Ete   O  1 1 29                              2865                                                                             3,4-Dbp                                                                            H    H    C S -- --   -- --    -- 0 0 29                              2866                                                                             3,4-Dbp                                                                            H    H    C S O  Me   O  --    -- 0 1 29                              2867                                                                             3,4-Dbp                                                                            H    H    C S O  Me   S  --    -- 0 1 29                              2868                                                                             3,4-Dbp                                                                            H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 29                              2869                                                                             3,4-Dbp                                                                            H    H    C S Mee                                                                              H    O  --    -- 0 1 29                              2870                                                                             3,4-Dbp                                                                            H    H    C S Mee                                                                              H    S  --    -- 0 1 29                              2871                                                                             3,4-Dbp                                                                            H    H    C S Phe                                                                              H    O  --    -- 0 1 29                              2872                                                                             3,4-Dbp                                                                            H    H    C S NH Pr   O  Ete   O  1 1 29                              2873                                                                             3,4-Dbp                                                                            H    H    C S O  Me   NH Trim  -- 1 1 29                              2874                                                                             9-Ant                                                                              H    H    C S O  H    O  Ete   O  1 1 29                              2875                                                                             9-Ant                                                                              H    H    C S S  H    O  Ete   O  1 1 29                              2876                                                                             9-Ant                                                                              H    H    C S -- --   -- --    -- 0 0 29                              2877                                                                             9-Ant                                                                              H    H    C S O  Me   O  --    -- 0 1 29                              2878                                                                             9-Ant                                                                              H    H    C S O  Me   S  --    -- 0 1 29                              2879                                                                             9-Ant                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 29                              2880                                                                             9-Ant                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 29                              2881                                                                             9-Ant                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 29                              2882                                                                             9-Ant                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 29                              2883                                                                             9-Ant                                                                              H    H    C S NH Pr   O  Ete   O  1 1 29                              2884                                                                             9-Ant                                                                              H    H    C S O  Me   NH Trim  -- 1 1 29                              2885                                                                             2-Npe                                                                              H    H    C S O  H    O  Ete   O  1 1 29                              2886                                                                             2-Npe                                                                              H    H    C S S  H    O  Ete   O  1 1 29                              2887                                                                             2-Npe                                                                              H    H    C S -- --   -- --    -- 0 0 29                              2888                                                                             2-Npe                                                                              H    H    C S O  Me   O  --    -- 0 1 29                              2889                                                                             2-Npe                                                                              H    H    C S O  Me   S  --    -- 0 1 29                              2890                                                                             2-Npe                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 29                              2891                                                                             2-Npe                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 29                              2892                                                                             2-Npe                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 29                              2893                                                                             2-Npe                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 29                              2894                                                                             2-Npe                                                                              H    H    C S NH Pr   O  Ete   O  1 1 29                              2895                                                                             2-Npe                                                                              H    H    C S O  Me   NH Trim  -- 1 1 29                              2896                                                                             Bdbbp                                                                              H    H    C S O  H    O  Ete   O  1 1 29                              2897                                                                             Bdbbp                                                                              H    H    C S S  H    O  Ete   O  1 1 29                              2898                                                                             Bdbbp                                                                              H    H    C S -- --   -- --    -- 0 0 29                              2899                                                                             Bdbbp                                                                              H    H    C S O  Me   O  --    -- 0 1 29                              2900                                                                             Bdbbp                                                                              H    H    C S O  Me   S  --    -- 0 1 29                              2901                                                                             Bdbbp                                                                              H    H    C S O  2-ClPh                                                                             O  --    -- 0 1 29                              2902                                                                             Bdbbp                                                                              H    H    C S Mee                                                                              H    O  --    -- 0 1 29                              2903                                                                             Bdbbp                                                                              H    H    C S Mee                                                                              H    S  --    -- 0 1 29                              2904                                                                             Bdbbp                                                                              H    H    C S Phe                                                                              H    O  --    -- 0 1 29                              2905                                                                             Bdbbp                                                                              H    H    C S NH Pr   O  Ete   O  1 1 29                              2906                                                                             Bdbbp                                                                              H    H    C S O  Me   NH Trim  -- 1 1 29                              2907                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 30                              2908                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 30                              2909                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 30                              2910                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 30                              2911                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 30                              2912                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 30                              2913                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 30                              2914                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 30                              2915                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 30                              2916                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 30                              2917                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 30                              2918                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 31                              2919                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 31                              2920                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 31                              2921                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 31                              2922                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 31                              2923                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 31                              2924                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 31                              2925                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 31                              2926                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 31                              2927                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 31                              2928                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 31                              2929                                                                             3,4-Dbp                                                                            H    H    C O O  H    O  Ete   O  1 1 32                              2930                                                                             3,4-Dbp                                                                            H    H    C O S  H    O  Ete   O  1 1 32                              2931                                                                             3,4-Dbp                                                                            H    H    C O -- --   -- --    -- 0 0 32                              2932                                                                             3,4-Dbp                                                                            H    H    C O O  Me   O  --    -- 0 1 32                              2933                                                                             3,4-Dbp                                                                            H    H    C O O  Me   S  --    -- 0 1 32                              2934                                                                             3,4-Dbp                                                                            H    H    C O O  2-ClPh                                                                             O  --    -- 0 1 32                              2935                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    O  --    -- 0 1 32                              2936                                                                             3,4-Dbp                                                                            H    H    C O Mee                                                                              H    S  --    -- 0 1 32                              2937                                                                             3,4-Dbp                                                                            H    H    C O Phe                                                                              H    O  --    -- 0 1 32                              2938                                                                             3,4-Dbp                                                                            H    H    C O NH Pr   O  Ete   O  1 1 32                              2939                                                                             3,4-Dbp                                                                            H    H    C O O  Me   NH Trim  -- 1 1 32                              __________________________________________________________________________

Of the compounds listed above, preferred compounds are Compound Nos. 1to 440, 454, 476, 586, 696, 806, 916, 1026, 1136, 1246, 1356, 1466,1576, 1686, 1763, 1773, 1793, 1979, 1980, 1990 to 1994, 2250 and 2326 to2906.

The more preferred compounds are Compound Nos. 1 to 110, 113, 221 to330, 333, 454, 1763, 1773, 1793, 1979, 1980, 1990 to 1994, 2250 and 2334to 2906.

The most preferred compounds are Compound Nos. 1, 2, 3, 4, 12, 13, 14,13, 2555, 2556, 2557, 2558, 2566, 2567, 2568, 2569, 2665, 2666, 2667,2668, 2676, 2677, 2678 and 2679.

The compounds of the present invention can be in the form of salts,especially pharmaceutically acceptable salts with cations. Examples ofsuitable salts include inorganic or organic salts, for example, thosewith alkali metals such as sodium or potassium, alkali earth metals suchas calcium; ammonia; basic amino acids such as lysine or arginine; andalkylamines such as triethylamine. Preferred salts are the alkali metalsalts such as sodium or potassium.

Some methods for the preparation of the compounds of the presentinvention are illustrated by the following reaction schemes.

In general, the compounds of general formula (1) can be prepared bycondensing a suitably derivatized nucleotide, being the nucleotide atthe 5'-end of the desired compound, with a protected oligonucleotidelacking a 5'-end nucleotide, the nucleotides of the lackingoligonucleotide giving with the said 5'-end nucleotide the appropriatenucleotide sequence of the desired oligodeoxyribonucleotide compound,the protected lacking nucleotide being linked to a polymer support.Typically the process involves reacting a compound R¹ R² R³ Z--Y'-5'-end nucleotide! with a compound protector!- lackingoligonucleotide!-linker-polymer.

More concretely, the present invention provides a process whichcomprises condensing a compound of the following formula (2) with acompound of the kind protector!-O-F-W, where F is the lackingoligonucleotide and W is the linker and polymer support. Using DMT asprotector, examples of compounds for reacting with compound (2) includecompounds of formulae: DMT-O-F-W₁ (3), DMT-O-F-W_(2a) (4a),DMT-O-F-W_(2b) (4b), DMT-O-F-W₃ (5), DMT-O-F-W_(4a) (6a), DMT-O-F-W_(4b)(6b), DMT-O-F-W_(4c) (6c), DMT-O-F-W_(4d) (6d), DMT-OF-W_(5a) (7a), andDMT-O-F-W_(5b) (7b), according to Method C-1, C-2 or C-3. The reactant(2) used in this reaction can suitably be prepared by Method A-1 or A-2and the reactants (3, 4a, 4b, 5, 6a to 6d, 7a and 7b) can suitably beprepared by Method B-1, B-2, B-3, B-4 or B-5. ##STR3## Method A-1##STR4## Method A-2 ##STR5## Method B-1 ##STR6## Method B-2 ##STR7##Method B-3 ##STR8## Method B-4 ##STR9## Method B-5 ##STR10## Method C-1##STR11## Method C-2 ##STR12## Method C-3 ##STR13##

In the various compounds of general formula (2), R₁, R₂, R₃, Y₁ and Zare as defined for the said general formula (1); D' represents a baseselected from the following "5'-base group" or the correspondingprotected base, the base being the base at the 5'-end moiety of the saideffective base sequence (hereafter designated as the 5'-end moiety ofthe said effective base sequence or simply the 5'-end base), where the"5'-base group" is adenine, guanine, cytosine, thymine or5-methylcytosine.

Method B-1 involves the preparation of a compound (3) lacking onenucleotide fragment from the 5' end of the said effective sequence,synthesized by using controlled pore glass (hereafter designated as CPG)comprizing a linker bonded with a protected nucleoside usable for DNAsynthesis of the 3'-end moiety of the said effective base sequence(hereafter designated as a 3'-end nucleoside) and a nucleotide unitcommercialized for a DNA synthesizer (hereafter designated as anucleotide unit).

Method B-2 involves the preparation of a compound (4a) having onenucleotide short fragment from 5' end of the said effective sequencesynthesized by protecting one terminal hydroxyl group of C₂ -C₁₀-alkylenediol having hydroxyl groups at the terminal positions or thealkylenediol having protected hydroxyl or amino groups with adimethoxytrityl (DMT) group, reacting the other hydroxyl group withsuccinic anhydride to produce a succinic acid monoester, bonding acarboxyl group of the monoester to CPG, removing the terminal DMT group,and finally reacting a nucleotide unit with the CPG-bound alkylenealcohol (4-6) in regular sequence on a DNA synthesizer; and thepreparation of a compound (4b) by converting the CPG-bound alkylenealcohol (4-6) to 3'-end nucleoside phosphorothioate supported by CPG(4-7) according to conventional means used in preparing thioatenucleotide on a DNA synthesizer and then reacting with a nucleotide unitin the same way as above.

Method B-3 involves the preparation of a compound (5) having onenucleotide short fragment from 5' end of the said effective sequencesynthesized by condensing 3'-end nucleoside phosphonate, which isprepared by reacting a hydroxyl group at the 3'-position of the 3'-endnucleoside with phosphonic acid to produce an ester linkage, with aCPG-bound ethylene glycol (5-1) prepared by the use of succinicanhydride in Method B-2, reacting with alkylamine to produce 3'-endnucleoside phosphoramidite supported by CPG (5-4) and finally reactingwith a nucleotide unit in a regular sequence on a DNA synthesizer.

Method B-4 involves the preparation of a known compound (6-3) M. Durandet al., Nucleic Acids Res., 18, 6353(1990)! by protecting one hydroxylgroup of hexaethylene glycol with a DMT group and reacting the otherhydroxyl group with a reagent for preparing phosphoramidite group.

Subsequently in analogy with the procedure described in Method B-3,CPG-bound DMT-protected glycol (6-6) can be prepared by condensing thesaid hexaethylene glycol protected with a DMT group (6-2) to CPG by theuse of succinic acid.

After removal of a DMT group from CPG-bound DMT-protecting glycol (6-6)on a DNA synthesizer, the glycol is reacted with a nucleotide unit togive the desired compound (6a) having one nucleotide short fragment from5' end of the said effective sequence synthesized. The glycol supportedon CPG, which is obtained by removal of a DMT group from CPG-boundDMT-protected glycol (6-6) on a DNA synthesizer, is reacted once, twiceor thrice with the said phosphoramidite followed by reacting with anucleotide unit comprizing one nucleotide short fragment from the 5'-endof the said effective base sequence to produce a compound of formulae(6b), (6c) or (6d), respectively.

Method B-5 involves the preparation of a compound (7-3) by deprotectinga DMT group from commercially available protected 2'-deoxynucleosidesupported by CPG through a linker (hereafter designated as D'"-CPG) andreacting with(2-cyanoethoxy)-2-(2'-O-4,4'-dimethoxytrityloxyethylsulfonyl)ethoxy-N,N-diisopropylaminophosphine(7-1) reported by T. Horn et al., in Tetrahedron Letters, 27,4705(1986); the preparation of a compound (7-5) by deprotecting a DMTgroup from the compound (7-3) prepared above and condensing thedeprotected compound with a compound (7-4) having an aryl or alkylphosphate of a hydroxyl group at the 3'-position of the 3'-endnucleoside using a condensing agent; and the preparation of a compound(7a) by reacting the compound (7-5) prepared above with a nucleotideunit comprizing one nucleotide short fragment from 5' end of the saideffective sequence synthesized.

In a similar manner as above a compound (7-7) can be prepared byreacting a compound (7-3) freed from a DMT group with a compound (7-6)having an alkyl or aryl phosphoramidite group at the 3'-position of the3'-end nucleoside and treating in analogy with the synthesis ofphosphoric acid triester or phosphorothioate triester on a DNAsynthesizer. The product thus obtained is reacted with a nucleotide unitin regular sequence to produce a compound (7a) having one nucleotideshort fragment from the 5'-end of the said effective base sequence.

Method C-1 involves the preparation of the desired compound of generalformula (1) by reacting a compound (2) with a phosphitylating agent toproduce a 3'-phosphate derivative (8), reacting the product thusobtained with each oligomer of formulae (3, 4a, 4b, 5, 6a to 6d, 7a and7b) supported on CPG, which is prepared in Methods B-1 to B-5, afterdeprotection of a DMT group, oxidizing the condensed product by anoxidising agent, cleaving the nucleotide chain from the CPG, and finallyremoving a protecting group excepting the substituent moiety bonded to acarbon atom at the 5'-position of the 5'-end nucleoside.

Method C-2 involves the preparation of the desired compound (1) byreacting a compound (2) with a phosphorylating agent to produce a3'-phosphoric acid derivative (9), condensing the product with the saidcompound each of formulae: (3, 4a, 4b, 5, 6a to 6d, 7a and 7b) afterdeprotection of a DMT group alone to form a phosphoric acid triesterlinkage, cleaving the nucleotide chain from the CPG, removing aprotecting group excepting the substituent moiety bonded to a carbonatom at the 5'-position of the 5'-end nucleoside; and finally purifyingby conventional means.

Method C-3 involves the desired compound (1) by introducing a phosphonicacid group into the 3'-position of a compound (2) to produce a compound(10), condensing the product with the said compound each of formulae:(3, 4a, 4b, 5, 6a to 6d, 7a and 7b) by the use of acid halide in thepresence of a base, oxidizing the condensed product by an oxidizingagent to form a phosphoric acid diester linkage, cleaving the nucleotidefrom CPG, removing a protecting group excepting the substituent moietybonded to a carbon atom at the 5'-position of the 5'-end nucleoside, andfinally purifying by conventional means.

Method A to Method C are explained in great detail as follows.

In the reaction schemes summarized in Methods A to Method C, R₁, R₂, R₃,R₄, Z, Y₁, Y₂, Y₃, Y₄, X, n, m and B are as defined above; A₁ representsa trityl (Tr) group, a monomethoxytrityl (MMT) group or adimethoxytrityl (DMT) group which is generally used for protectingspecifically a primary hydroxyl group of nucleoside; and A₂ represents atri-substituted silyl group such as a tert-butyldimethylsilyl (TBDMS) ortriisopropylsilyl (TIPS) group; a trihalogenoethoxycarbonyl group suchas trichloroethoxycarbonyl (Troc) group; or an aralkyloxycarbonyl groupsuch as a benzyloxycarbonyl (Z) group.

D' represents a base of the 5'-end nucleotide, an amino group of whichis protected with an acyl group for synthesizing DNA of the saideffective base sequence; D" represents a base moiety of nucleotide atthe 3'-end; and D'" represents a base moiety of the optional nucleotideunit to be used in the DNA synthesis, that is, a base selected from the5'-base group or the corresponding protecting base.

F is an oligonucleotide part having one nucleotide short fragment from5' end of the said effective sequence and represents a base part or thecorresponding oligonucleotide protected with a protecting group of aphosphoric acid part, which is generally used for DNA synthesis but doesnot contain any hydroxyl gorup at the 5'-position of the 5'-endnucleoside and at the 3'-positions of the 3'-end nucleoside. Vrepresents a protecting group of a phosphoric acid part in the case ofDNA synthesis. U represents an amino group of an amidite part. W₁ to W₅represent a fragment of from CPG to an oxygen atom of a hydroxyl groupat the 3'-position of the 3'-end nucleotide of oligonucleotide (F) ofthe final desired compound according to the procedure described inMethod B-1 to B-5. 1 is an integer of 1 to 9; E represents a hydrogenatom or an optionally protected hydroxyl or amino group; and Krepresents an oxygen or sulfur atom.

R₅ represents a methyl, ethyl, propyl, butyl, phenyl, methoxy, ethoxy,propoxy, butoxy, cyanoethyloxy or optionally substituted phenyloxygroup.

Each of the following steps is explained in greater detail as follows.In case the step is capable of conducting in analogy with the proceduredescribed in the preceding one, the first one is explained as arepresentative.

(Steps 1, 8 and 18!

In these steps a compound (2-2), in which a hydroxyl group alone at the5'-position is selectively protected, can be prepared by reacting acompound (2-1) with a hydroxyl-protecting reagent in an inert solvent.Where a base part is A, G or C, amino groups comprizing in the base areprotected by acylation in the foregoing stage and the protectingreaction can be carried out in a manner known per se, for example inanalogy to the reported procedure J. Am. Chem. Soc., 104, 1316(1982)!.As an amino-protecting group there comes generally into consideration analiphatic lower acyl or aromatic acyl group. Examples of acyl groupsinclude: aliphatic lower acyl groups such as a formyl, acetyl,propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl orisovaleryl group; and aromatic acyl groups such as a benzoyl,4-acetoxybenzoyl, 4-methoxybenzoyl, 4-methylbenzoyl or 1-naphthoylgroup; preferably in case base part is A or C, a benzoyl group and incase a base part is G, an isobutyryl group.

Examples of preferred solvents to be include: aromatic hydrocarbons suchas benzene, toluene or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate or diethyl carbonate; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone orcyclohexanone; nitro compounds such as nitroethane or nitrobenzene;nitrites such as acetonitrile or isobutyronitrile; amides such asformamide, dimethylformamide (DMF), dimethylacetamide orhexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide orsulfolane; aliphatic tertiary amines such as trimethylamine,triethylamine or N-methylmorpholine; and aromatic amines such aspyridine or picoline; more preferably halogenated hydrocarbons(particularly dichloromethane) and amides (particularly DMF).

There is no particular limitation upon the nature of the reagent usedfor protection, provided that it can be used for specific protection ofa hydroxyl group alone at the 5'-position and is capable of removingunder acidic or neutral conditions. Example of preferred protectingreagents include triarylmethyl halides such as trityl chloride,monomethoxytrityl chloride or dimethoxytrityl chloride.

Where the protecting reagent is a triarylmethyl halide, the reaction isnormally carried out in the presence of a base.

Examples of suitable bases include: heterocyclic amines such aspyridine, dimethylaminopyridine or pyrrolidinopyridine; and aliphatictertiary amines such as trimethylamine or triethylamine; preferablyorganic bases (particularly pyridine, dimethylaminopyridine andpyrrolidinopyridine).

Where organic amines are used as a solvent, it is unnecessary to use theother deacidifying agent because the organic amines themselves act as adeacidifying agent.

The reaction temperature varies depending upon the nature of thestarting material and solvent used and other reaction conditions, butthe reaction is normally carried out at a temperature from 0° to 150°C., preferably 20° to 100° C.

The time required for the reaction varies depending upon the nature ofthe starting material and solvent used as well as the reactiontemperature, but the reaction is normally complete within a period of 1to 100 hours, preferably 2 to 24 hours.

After completion of the reaction, the desired compound can be isolatedfrom the reaction mixture, for example, by pouring the reaction mixtureinto water, extracting with a water-immiscible solvent such as benzene,ether or ethyl acetate, and finally distilling off the solvent from theextract. The product thus obtained can be used in the subsequentreaction without further purification but if desired, can be purified byconventional means, for example, various chromatography orrecrystallization.

Step 2!

In this step a compound (2-3) can be prepared by reacting a compound(2-2) with a hydroxyl-protecting reagent in the presence of an inertsolvent.

Examples of preferred solvents include: aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate, diethyl carbonate; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone orcyclohexanone; nitro compounds such as nitroethane or nitrobenzene;nitriles such as acetonitrile or isobutyronitrile; amides such asformamide, dimethylformamide, dimethylacetamide or hexamethylphosphorictriamide; sulfoxides such as dimethylsulfoxide or sulfolane; morepreferably ethers (particularly tetrahydrofuran), halogenatedhydrocarbons (particularly dichloromethane), aromatic hydrocarbons(particularly toluene) and amides (particularly DMF).

There is no particular limitation upon the nature of thehydroxyl-protecting reagent used, provided that the protecting group canbe deprotected in distinction from a protecting group at the5'-position. Examples of such protecting reagents include: silyl halidessuch as tert-butyldimethylsilyl chloride or triisopropylsilyl chloride;haloalkoxycarbonyl halides such as trichloroethoxycarbonyl chloride; andaralkyloxycarbonyl halides such as benzyloxycarbonyl chloride.

Where the protecting reagent is silyl halides, haloalkoxycarbonylhalides or aralkyloxycarbonyl halides, the reaction for protection isnormally carried out in the presence of a base.

Examples of preferred bases include organic bases (particularlytriethylamine, pyridine, N-methylmorpholine, DBU and imidazole).

The reaction temperature varies depending upon the nature of thereagent, starting compound and solvent and other reaction conditions,but the reaction is normally carried out at a temperature of -20° to150° C., preferably -10° to 50° C.

The time required for the reaction varies depnding upon the nature ofthe starting compound and solvent used as well as the reactiontemperature, but the reaction is normally complete within a period of 1to 100 hours, preferably 1 to 24 hours.

After completion of the reaction, the desired compound can be isolatedfrom the reaction mixture. An example of one such technique comprises:pouring the reaction mixture into water; extracting with awater-immiscible solvent such as benzene, ether or ethyl acetate; andfinally distilling off the solvent from the extract. The product thusobtained can normally be used in the subsequent reaction without furtherpurification but if desired, can be purified by various chromatography,recrystallization or the like means

Step 3, 11, 22 and 25!

In these steps, compounds (2-4), (4-6), (6-7) and (6-9) can be preparedby reacting compound (2-3), (4-5), (6-6) and (6-8) with a deprotectingreagent in the presence of an inert solvent to remove selectively thehydroxyl-protecting group at the 5'-position.

Examples of preferred solvents include: aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate or diethyl carbonate; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether, alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,cyclohexanol or methyl cellosolve; ketones such as acetone, methyl ethylketone, methyl isobutyl ketone, isophorone or cyclohexanone; nitrocompounds such as nitroethane or nitrobenzen; nitrites such asacetonitrile or isobutyronitrile; amides such as formamide,dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;and sulfoxides such as dimethylsulfoxide or sulfolane; more preferablyalcohols (particularly methanol and ethanol) and dichloromethane, and incase acetic acid is a deprotecting reagent, a mixture of acetic acid andwater.

There is no particular limitation upon the nature of the deprotectingreagent used, provided that it can normally be used for conventionaldeprotection. Where the protecting group is a triarylmethyl group, itcan be removed by using acids such as acetic acid, dichloroacetic acid,trifluoroacetic acid, hydrochloric acid or Lewis acids such as zincbromide, preferably acetic acid, dichloroacetic acid or trifluoroaceticacid.

The reaction temperature varies depending upon the nature of thereagent, starting compound and solvnet used and other reactionconditions, but the reaction is normally carried out at a temperature of-10° to 100° C., preferably 0° to 50° C. The time required for thereaction varies depending upon the nature of the starting compound andsolvent used as well as the reaction temperature, but the reaction isnormally complete within a period of 1 minute to 50 hours, preferably 1minute to 24 hours.

After completion of the reaction, the desired compound can be isolatedfrom the reaction mixture. In Step 3, an example of one such techniquecomprises: neutralizing the reaction mixture, pouring it into water;extracting with a water-immiscible solvent such as benzene, ether orethyl acetate; and distilling off the solvent from the extract. Theproduct thus obtained can normally be used in the subsequent reactionwithout further purification but if desired, can be purified by variouschromatography, recrystallization or the like means. In Steps 11, 22 and25, an example of one such technique comprises: separating the desiredcompound by filtration and washing it with methylene chloride.

Steps 4 and 6!

In these steps a compound (2-6) or (2) can be prepared by reacting acompound (2-4) or (2-1) with a compound (2-5) (in the formula, Halsignifies a halogen atom) in the presence of an inert solvent and abase. The halide moiety of the compound (2-5) used is exemplified bychlorine, bromine or iodine, preferably chlorine or bromine.

Examples of preferred solvents include: aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate or diethyl carbonate; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone orcyclohexanone; nitro compounds such as nitroethane or nitrobenzen;nitriles such as acetonitrile or isobutyronitrile; amides such asformamide, dimethylformamide, diemthylacetamide or hexamethylphosphorictriamide; and sulfoxides such as dimethylsulfoxide or sulfolane; morepreferably ethers (particularly tetrahydrofuran), ketones (particularlyacetone), halogenated hydrocarbons (particularly dichloromethane),amides (particularly DMF) and aromatic amines (particularly pyridine).

Examples of preferred bases include: organic bases (particularlytriethylamine, pyridine, N-methylmorpholine, DBU and the like base),alkali metal hydrides (particularly sodium hydride) and alkali metalcarbonates (particularly sodium carbonate and lithium carbonate), and incase Z of the compound (2-5) is a silicon atom, imidazole is the mostpreferable organic base.

The reaction temperature is not particularly critical, but the reactionis normally carried out at a temperature of 0° to 100° C., preferably20° to 60° C.

The time required for the reaction ranges normally from 5 minutes to 30hours. When the reaction is carried out at 50° C., it is complete withina period of 10 hours.

After completion of the reaction, the desired compound can be isolatedfrom the reaction mixture, for example, by neutralizing properly thereaction mixture of filtering off insoluble materials if any, addingwater and a water-immiscible organic solvent such as ethyl acetatethereto, separating the organic layer containing the desired compound,washing the extract with water, drying the extract over anhydrousmagnesium sulfate etc., and finally distilling off the solvent. Thedesired compound thus obtained, if necessary, can be purified byconventional means, for example, recrystallization, reprecipitation,chromatography or the like means.

Step 5!

In this step a compound (2) can be prepared by reacting a compound (2-6)with a deprotecting reagent in the presence of an inert solvent.

(1) Where a hydroxyl-protecting group at the 3'-position is a silylgroup, it can normally be removed by treating with a compound capable ofproducing a fluoride ion such as tetrabutylammonium fluoride.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Preferredexamples include ethers such as tetrahydrofuran or dioxane.

The reaction temperature is not particularly critical but the reactionis normally carried out at a temperature of -30° to 100° C., preferably0° to 30° C.

The time required for the reaction ranges normally from 5 minutes to 30hours. When the reaction is carried out at 20° C., it is complete withina period of 10 hours.

After completion of the reaction, the desired compound can be isolatedfrom the reaction mixture, for example, by neutralizing properly thereaction mixture of filtering off insoluble materials if any, addingwater and a water-immiscible organic solvent such as ethyl acetatethereto, separating the organic layer containing the desired compound,washing the extract with water, drying the extract over anhydrousmagnesium sulfate etc., and finally distilling off the solvent. Thedesired product thus obtained, if necessary, can be purified byconventional means, for example, recrystallization, reprecipitation,chromatography or the like means.

The desired product thus obtained, if necessary, can be further purifiedby conventional menas, for exmaples, recrystallization, reprecipitation,chromatography or the like means.

(2) Where a hydroxyl-protecting group at the 3'-position is ahaloalkoxycarbonyl group, it can normally be removed by treating withzinc dust.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Examples ofpreferred solvents include acetic acid, alcohols or mixtures of waterand one or more of these solvents.

The reaction temperature is not particularly critical but the reactionis normally carried out at a temperature of 0° to 100° C., preferably atroom temperature.

The time required for the reaction is normally in a range of 5 minutesto 30 hours. Where the reaction is carried out at room temperature, itis complete within a period of 10 hours.

After completion of the reaction, the desired compound can be isolatedfrom the reaction mixture, For example, by neutralizing properly thereaction mixture or filtering off insoluble materials if any, addingwater and a water-immiscible organic solvent such as ethyl acetate,separating the organic layer containing the desired compound, washingthe extract with water, drying over anhydrous magnesium sulfate etc.,and finally distilling off the solvent. The reaction product thusobtained can be further purified by conventional means, for example,recrystallization, reprecipitation, chromatography or the like means.

(3) Where a hydroxyl-protecting group at the 3'-position is anaralkyloxycarbonyl group, it can normally be removed by catalyticreduction or oxidation.

There is no particular limitation upon the nature of the catalyst usablefor reduction, provided that it can usually be used in catalyticreduction. Examples of preferred catalysts include palladium oncharcoal, Raney nickel, platinum oxide, platinum black, rhodium onalumina, a combination of triphenylphosphine and rhodium chloride andpalladium on barium sulfate.

Hydrogen pressure, under which the reaction is carried out, is notparticularly critical, but the reaction is normally carried out in arange of 1 to 10 atmospheric pressure.

The reaction temperature and the time required for the reaction varydepending upon the nature of the starting compound and solvent used aswell as the type of the catalyst and other reaction conditions, but thereaction is carried out at a temperature of 0° to 100° C. and it iscomplete within a period of 5 minutes to 24 hours.

There is no particular limitation upon the nature of the solvent to beused in the deprotection by oxidation, provided that it has no adverseeffect upon the reaction. Preferred solvent are exemplified by mixturesof water and one or more of organic solvents.

Examples of preferred organic solvents include: ketones such as acetone;halogenated hydrocarbons such as dichloromethane, chloroform or carbontetrachloride; nitriles such as acetonitrile; ethers such as diethylether, tetrahydrofuran or dioxane; amides such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; and sulfoxides suchas dimethylsulfoxide.

There is no particular limitation upon the nature of the oxidizing agentused, provided that it can be used in conventional oxidation. Preferredexamples are exemplified by potassium persulfate, sodium persulfate,ammonium cerium nitrate (CAN) and2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature and the time required for the reaction varydepending upon the nature of the starting compound and solvent as wellas the type of the catalyst used and other conditions, but the reactionis normally carried out at a temperature of 0° to 150° and it iscomplete within a period of 10 minutes to 24 hours.

The hydroxyl-protecting group can also be removed by treating withalkali metals such as lithium metal or sodium metal in liquid ammonia oralcohols such as methanol or ethanol at a temperature of -78° to -20° C.

Further the protecting group can be removed by using a combination ofaluminium chloride and sodium iodide or alkylsilyl halides such astrimethylsilyl iodide in a solvent.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Preferredsolvents are exemplified by nitrites such as acetonitrile, halogenatedhydrocarbons such as dichloromethane or chloroform and mixtures of twoor more of these solvents.

The reaction temperature and the time required for the reaction varydepending upon the nature of the starting compound and solvent and otherreaction conditions, but the reaction is normally carried out at atemperature of 0° to 50° C. and it is complete within a period of 5minutes to 3 days.

Where the substrate contains a sulfur atom, the deprotection canpreferably be achieved using a combination of aluminium chloride andsodium iodide.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture, for example, by neutralizing properly the reactionmixture or filtering off insoluble materials if any, adding water and awater-immiscible organic solvent such as ethyl acetate thereto,separating the organic layer containing the desired compound, washingthe extract with water, drying over anhydrous magnesium sulfate etc.,and finally distilling off the solvent. The desired compound thusobtained, if necessary, can be further purified by conventional means,for example, recrystallization, reprecipitation, chromatography or thelike means.

Steps 7, 12, 14, 17, 23, 26, 28, 30, 33 and 35!

In these steps, CPG-bond oligodeoxyribonucleotides (3), (4a), (4b), (5),(6a) to (6d), (7a) and (7b) can be prepared by using CPG-bondnucleosides comprizing the 3'-end nucleosides of the said effective basesequence, repeating the elongation step of DNA chain on a DNAsynthesizer, and finally preparing one nucleotide short fragment from 5'end of the said effective sequence.

The elongation of DNA chain on a DNA synthesizer is explained accordingto the "phosphoramidite" approach but it is understood that this methodis for the purpose of description and not of limitation.

In Step 7 commercially available CPG-bound D" (3-1) is treated with adeprotecting reagent of a DMT group on a DNA synthesizer to remove a5'-terminal DMT group and then it is condensed with a nucleotide unitcommercialized for a DNA synthesizer followed by forming a phosphorousacid triester linkage, which is subsequently oxidized to phosphoric acidtriester by using a proper oxidizing agent. After synthesizing onenucleotide short fragment from 5' end of the said effective sequence byrepeating these steps, there is prepared CPG-bond ODN (3) having a5'-terminal DMT group. The CPG-bound ODN of the desired nucleotide basesequence, the 5'-terminal of which is protected with a DMT group, can besynthesized according to the procedure reported by H. Koster et al. inNucleic Acid Res., 12, 4539(1984) or its modified procedure using asynthesizer based on a phosphoramidite method, for example, Model 380B(a product of Applied Biosystems Inc.) or Cyclon Plus (a product ofMilliGen/Biosearch).

A base moiety of the nucleotide unit to be used for synthesizing ODN isthose which is protected with an acyl group. Preferred acyl groups areexemplified by a benzoyl group in case the base moiety is A or C and aisobutyryl group in case it is G.

Examples of the acidic substances to be used as a catalyst in thecondensing reaction of the step include acidic substances includingtetrazoles, preferably tetrazole.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Preferredsolvents are exemplified by acetonitrile and tetrahydrofuran.

The reaction is carried out at a temperature of from -30° to 50° C.,normally at room temperature.

The time required for the reaction varies depending upon the reactiontemperature but the reaction is complete within a period of 1 minute to20 hours. When the reaction is carried out at room temperature, it iscomplete within 10 minutes.

There is no particular limitation upon the nature of the oxidizing agentused in these steps, provided that it can be used in conventionaloxidation as an oxidizing agent. Examples of preferred oxidizing agentsinclude: inorganic metal oxidizing agents including manganese oxidessuch as potassium permanganate or manganese dioxide; ruthenium oxidessuch as ruthenium tetraoxide; selenium compounds such as seleniumdioxide; iron compounds such as ferric chloride; osmium compounds suchas osmium tetraoxide; silver compounds such as silver oxide; mercurycompounds such as mercuric acetate; lead oxide compounds such as leadoxide or lead tetraoxide; chromic acid compounds such as potassiumchromate, a complex of chromium sulfate and sulfuric acid or a complexof chromic acid and pyridine; cerium compounds such as cerium ammoniumnitrite (CAN); inorganic oxidizing agents including halogen moleculessuch as chlorine, bromine or iodine molecule; periodates such as sodiumperiodate; ozone; hydrogen peroxide; nitrous compounds such as nitrousacid; chlorous acid compounds such as potassium chlorite or sodiumchlorite; persulfuric acid compounds such as potassium persulfate orsodium persulfate; organic oxidizing agents including reagents used inDMSO oxidation (a complex of dimethylsulfoxide anddicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride orphosphorus pentaoxide, or a complex of pyridine and sulfur trioxide);peroxides such as tert-butyl hydroperoxide; stable cations such astriphenylmethyl cation; succinimides such as N-bromosuccinimide;hypochlorous acid compounds such as tert-butyl hypochlorite;azodicarboxylic acid compounds such as azodicarboxylate; a combinationof triphenylphosphine and disulfides such as dimethyl disulfide ordiphenyl disulfide; nitrous esters such as methyl nitrite;tetrahalogenocarbons such as tetrabromomethane; quinones such as2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ); preferably iodine.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Examples ofpreferred solvents include: aromatic hydrocarbons such as benzene,toluene or xylene; halogenated hydrocarbons such as dichloromethane orchloroform; ethers such as ether, tetrahydrofuran, dioxane ordimethoxyethane; amides such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol or isoamyl alcohol; diluted acids such as aqueous sulfricacid; diluted bases such as an aqueous solution of sodium hydroxide;water; ketones such as acetone or methyl ethyl ketone; heterocyclicamines such as pyridine; and nitriles such as acetonitrile; preferablyheterocyclic amines (particularly pyridine), nitriles (particularlyacetonitrile), ethers (particularly tetrahydrofuran) and halogenatedhydrocarbons (particularly dichloromethane).

The reaction is carried out at a temperature from -50° to 100° C. Thetime required for the reaction varies mainly depending upon the reactiontemperature as well as the nature of the starting compound and solventbut the reaction is carried out at a temperature of -50° to 100° C. andit is normally complete within a period of 30 minutes to 15 hours. Theoxidation reaction described abvoe is accelerated by adding aphase-transfer catalyst such as triethylbenzylammonium chloride ortributylbenzylammonium bromide.

Steps 12, 14, 17, 23, 26, 28, 30, 33 and 35 are similar.

Steps 9 and 20!

In these steps a half ester of dicarboxylic acid can be prepared byreacting a free hydroxyl group of a compound (4-2) or (6-2) with ananhydride of dicarboxylic acid such as succinic anhydride in thepresence of a base catalyst.

There is no particular limitation upon the nature of the dicarboxylicacid used. Preferred dicarboxylic acids are those which contain 2 to 10carbon atoms and the most preferred dicarboxylic acid is succinic acidor glutaric acid. Examples of suitable base catalysts include:aminopyridines such as dimethylaminopyridine or pyrrolidinopyridine;tertiary amines such as trimethylamine or triethylamine; sodiumhydrogencarbonate; and alkali metal carbonates such as potassiumcarbonate; most preferably dimethylaminopyridine or pyrrolidinopyridine.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction and is capableof dissolving the starting material in some extent. Examples ofpreferred solvents include: aromatic hydrocarbons such as benzene,toluene or xylene; halogenated hydrocarbons such as dichloromethane orchloroform; ethers such as ether, tetrahydrofuran, dioxane ordimethoxyethane; amides such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol or isoamyl alcohol; diluted acids such as aqueous sulfuricacid; diluted bases such as an aqueous solution of sodium hydroxide;water; ketones such as acetone or methyl ethyl ketone; heterocyclicamines such as pyridine; and nitrites such as acetonitrile; morepreferably nitriles (particularly acetonitrile), ethers (particularlytetrahydrofuran) and halogenated hydrocarbons (particularlydichloromethane).

The reaction is carried out at a temperature of -50° to 100° C. The timerequired for the reaction varies mainly depending upon the reactiontemperature as well as the nature of the starting compound and solventused, but the reaction is normally complete within a period of 30minutes to 15 hours.

Steps 10 and 21!

In these steps the desired compounds (4-5) and (6-6) can be prepared byreacting half esters of succinic acid (4-3) and (6-4) prepared in Steps9 and 20 with phenols such as pentachlorophenol in the presence of acondensing agent to produce an activated ester and subsequently reactingthe product with CPG-amines (4-4) and (6-5) in the presence of a base.

There is no particular limitation upon the nature of phenols used inthis reaction. Preferred phenols are exemplified by pentachlorophenoland 4-nitrophenol.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction and is capableof dissolving the starting material in some extent. Examples of suitablesolvents include: amides such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide;ketones such as acetone or methyl ethyl ketone; heterocyclic amines suchas pyridine; and nitrites such as acetonitrile; preferably amides suchas dimethylformamide.

There is no particular limitation upon the nature of the base used,provided that it can be used as a base in conventional reaction.Examples of preferred bases include: organic bases such astriethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazabicyclo 4,3,0!non-5-ene, 1,4-diazabicyclo2,2,2!octane (DABCO) or 1,8-diazabicyclo 5,4,0!undec-7-ene (DBU); morepreferably organic bases, particularly triethylamine, pyridine,N-methylmorpholine and DBU.

The reaction is carried out at a temperature of -50° to 100° C. The timerequired for the reaction varies mainly depending upon the reactiontemperature as well as the nature of the starting compound or solventused, but when the reaction is carried out at room temperature, it isnormally complete within a period of 30 to 50 hours.

Steps 13 and 32!

In Step 13 CPG-bound nucleoside (4-7) containing a thioate group can beprepared by reacting a compound (4-6) prepared in Step 11 with acommercially available 5'-O-DMT-nucleoside-3'-phosphoramidite reagent ona DNA synthesizer and subsequently reacting with a thioating reagent.

There is no particular limitation upon the nature of the thioatingreagent used, provided that it is capable of forming a thioate group byreacting with trivalent phosphorus. Exmaples of preferred thioatingreagents include: in addition to sulfur, tetraethylthiuram disulfide(TETD) (a product of Applied Biosystems Inc.) and Beaucage reagent (aproduct of MilliGen/Biosearch). The desired compound (4-7), in which3'-end nucleoside of the said effective base sequence is supported onCPG through a thioate group, can be prepared by treating withtetraethylthiuram disulfide (TETD) according to the procedure reportedin Tetrahedron Letters, 32, 3005(1991) or with Beaucage reagentaccording to the procedure reported in J. Am. Chem. Soc., 112,1253(1990) or its modified procedure.

In Step 32 CPG-bound nucleoside (7-7) having a phosphoric triester orthioate grouop can be prepared by reacting a compound (7-3) with aphosphoramidite reagent followed by treating by conventional means orwith a thioating agent.

Step 15!

In the step a CPG-bound compound (5-3) having a phosphonic acid diestergroup can be prepared by reacting a CPG-bound compound (5-1) freed froma DMT group, which is obtained in analogy with the preparation of aCPG-bound compound (4-6), with a commercially available phosphonic acidmonoester compound (5-2) in the presence of a condensing agent and adeacidifying agent. There is no particular limitation upon the nature ofthe condensing agent used, provided that it can be formed an acidanhydride with phosphonic acid monoester. Examples of preferredcondensing agents include adamantane-1-carbonyl chloride and pivaloylchloride. There is no particular limitation upon the nature of thedeacidifying agent used, provided that it can be used as a deacidifyingagent in case acylation is carried out using an acid chloride. Examplesof preferred deacidifying agents, in general, include aromatic aminessuch as pyridine. There is no particular limitation upon the nature ofthe solvent used, provided that it has no adverse effect upon thereaction. Examples of preferred solvents include nitriles such asanhydrous acetonitrile. When the reaction is carried out at roomtemperature, it is complete within a period of 5 to 60 minutes.

Step 16!

In the step a phosphonic acid diester group of a CPG-bound compound(5-3) is transformed to a phosphoramidate group by reacting withalkylamine and carbon tetrachloride. As alkylamine there are to beunderstood the desired alkylamines. There is no particular limitationupon the nature of the solvent used, provided that it has no adverseeffect upon the reaction. Examples of preferred solvents includenormally non-polar solvents such as carbon tetrachloride. The reactiontemperature is not particularly critical and the reaction is normallycarried out at a temperature from -50° to 100° C. When the reaction isconducted at room temperature, it is complete within a period 1 to 10hours.

Steps 19 and 36!

In these steps 3'-phosphorous acid derivatives (6-3) and (8) can beprepared by reacting compounds (6-2) and (2) with chlorophosphoramidite(6-3'), which is used as a phosphitylating agent, in the presence of aninert solvent and a deacidifying agent. U used in the definition of acompound (6-3') signifies a dialkylamino group such as a dimethylaminoor diisopropylamino group or a heterocyclic group having 1 or 2 oxygenand/or nitrogen atoms in the ring. V used in the definition of acompound (6-3') may be any group, provided that it can be removed afterforming a phosphate bond. Examples of such groups include preferablylower alkyloxy groups such as a methoxy group and cyanoalkyloxy groupssuch as cyanoethyloxy group. As the compound (6-3') there are to beunderstood especially phosphines such aschloromorpholinomethoxyphosphine, chloromorpholinocyanoethoxyphosphine,chlorodimethylaminomethoxyphosphine,chlorodimethylaminocyanoethoxyphosphine,chlorodiisopropylaminomethoxyphosphine andchlorodiisopropylaminocyanoethoxyphosphine; preferablychloromorpholinomethoxyphosphine, chloromorpholinocyanoethoxyphosphine,chlorodiisopropylaminomethoxyphosphine andchlorodiisopropylaminocyanoethoxyphosphine.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Preferredsolvents are ethers such as tetrahydrofuran, diethyl ether or dioxane.Examples of deacidifying agents include: heterocyclic amines such aspyridine or dimethylaminopyridine and aliphatic amines such astrimethylamine, triethylamine or diisopropylethylamine, preferablyaliphatic amines (particularly diisopropylethylamine).

The reaction temperature is not particularly critical, but the reactionis normally carried out at a temperature from -50° to 50° C., preferablyat room temperature.

The time required for the reaction varies depending upon the nature ofthe starting compound and reagent as well as the reaction temperature,but the reaction is normally complete within a period of 5 minutes to 30hours. When the reaction is preferably carried out at room temperature,it is complete within a period of 30 minutes.

The desired compound can be recovered from the reaction mixture, forexample, by neutralizing properly the reaction mixture or filtering offinsoluble materials if any, adding water and a water-immiscible solventsuch as ethyl acetate, separating the organic layer containing thedesired compound, washing the extract with water, drying over anhydrousmagnesium sulfate etc., and finally distilling off the solvent.

The desired compound thus obtained, if necessary, can be furtherpurified by conventional means, if necessary, can be further purified byconventional means, for example, recrystallization, reprecipitation,chromatography or the like means.

Step 24!

In this step a CPG-bound compound (6-8) having a phosphoric triestergroup can be prepared in analogy with the procedure described in Step 7,but using a compound (6-3) instead of a nucleoside phosphoramiditecompound used as a nucleotide unit on a DNA synthesizer.

Steps 27 and 29!

In these steps CPG-bound compounds (6-10 and 6-11) having 2 or 3phosphoric triester groups can be prepared from a CPG-bound compound(6-9) prepared in Step 25 by treating in analogy with the proceduredescribed in Step 24.

Step 31!

In this step a CPG-bound compound (7-3) having a4,4'-dimethoxytrityloxyethylsulfonylethoxy group can be prepared bytreating a commercially available CPG-bound compound (7-2) freed from a5'-DMT group with (2-cyanoethoxy)-2-2'-O-(4,4'-dimethoxytrityloxyethylsulfonyl)ethoxy-N,N-diisopropylaminophosphine(7-1) T. Horn et al., Tetrahedron Letters, 27, 4705(1986)! in analogywith the procedure described in Step 24.

Step 34!

In the step a CPG-bound compound (7-5) can be preapred by deprotecting aDMT group from a CPG-bound compound (7-3) prepared in Step 31 and thencondensing with a nucleotide (7-4) having a DMT group at the 5'-positionand a group of alkyl phosphate, phenyl phosphate, alkyl phosphonate orphenyl phosphonate at the 3'-position by the use of a condensing agent.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Preferredsolvents are aromatic amines such as pyridine. As the condensing agentsthere come into consideration dicyclohexylcarbodiimide (DCC),mesitylenesulfonyl chloride (Ms-Cl), triisopropylbenzenesulfonylchloride, mesitylenesulfonyltriazole (MST),mesitylenesulfonyl-3-nitrotriazole (MSNT),triisopropylbenzenesulfonyltetrazole (TPS-Te),triisopropylbenzenesulfonylnitroimidazole (TPS-NI) andtriisopropylbenzenesulfonylpyridyltetrazole; preferably MSN, TPS-Te andTPS-NI.

The reaction temperature is not particularly critical but the reactionis carried out at a temperature of -10° to 100° C. The time required forthe reaction varies depending upon the nature of the solvent used andthe reaction temperature. When the reaction is carried out at roomtemperature using pyridine as a solvent, it is complete within a periodof 30 minutes.

Step 37!

In this step the final product (1) can be prepared by condensing acompound (8) prepared in Step 36 with CPG-bound ODN (3, 4a, 4b, 5, 6a to6d, 7a or 7b), which is synthesized on a DNA synthesizer and deprotecteda 5'-terminal DMT group alone, using an acid catalyst to form phosphatetriester, oxidizing using an appropriate oxidizing agent to producephosphoric acid triester, cleaving from CPG, removing the protectinggroups and finally purifying.

As an acid catalyst used in the condensing reaction there come intoconsideration acid substances such as tetrazoles; preferably tetrazole.

There is no particular limitation upon the nature of the oxidizing agentused, provided that it can be used as an oxidizing agent in oxidationreactions. Examples of preferred oxidizing agents include: inorganicmetal oxides including manganese oxides such as potassium permanganateor manganese dioxide; ruthenium oxides such as ruthenium tetraoxide;selenium oxides such as selenium dioxide; iron compounds such as ferricchloride; osmium compounds such as osmium tetraoxide; silver compoundssuch as silver oxide; mercuryl compounds such as mercury acetate; leadoxide compounds such as lead oxide or lead tetraoxide; chromic acidcompounds such as potassium chromate, a complex of chromic acid andsulfuric acid or a complex of chromic acid and pyridine; and ceriumcompounds such as cerium .ammonium nitrate (CAN); inorganic oxidizingagents including halogen molecules such as a chlorine, bromine or iodinemolecule; periodides such as sodium periodide; ozone; hydrogen peroxide;nitrous compounds such as nitrous acid; chlorous acid compounds such assodium chlorite; persulfate compounds such as potassium persulfate orsodium persulfate; and organic oxidizing agents including reagents usedin DMSO oxidation (a combination of dimethylsulfoxide anddicylcohexylcarbodiimide, oxalyl chloride, acetic anhydride orphosphorus pentachloride or a complex of pyridine and sulfuricanhydride); peroxides such as tert-butyl hydroperoxide; stable cationssuch as triphenylmethyl cation; succinimides such as N-bromosuccinimide;hypochlorous acid compounds such as tert-butyl hypochlorite;azodicarboxylic acid compounds such as azodicarboxylate; a combinationof disulfides such as dimethyl disulfide, diphenyl disulfide ordipyridyl disulfide and triphenylphosphine; nitrites such as methylnitrite; tetrahalogenated compounds such as tetrabromomethane; andquinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ);more preferably iodine.

There is no particular limitation upon the nature of the solvent used,provided chat it has no adverse effect upon the reaction and is capableof dissolving the starting materials in some extent. Examples ofpreferred solvents include: aromatic hydrocarbons such as benzene,toluene or xylene; halogenated hydrocarbons such as dichloromethane orchloroform; ethers such as ether, tetrahydrofuran, dioxane ordimethoxyethane; amides such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol or isoamyl alcohol; diluted acids such as aqueous sulfuricacid; diluted bases such as an aqueous solution of sodium hydroxide;water; ketones such as acetone or methyl ethyl ketone; heterocyclicamines such as pyridine; nitrites such as acetonitrile; preferablyheterocyclic amines (particularly pyridine), nitrites (particularlyacetonitrile), ethers (particularly tetrahydrofuran) and halogenatedhydrocarbons (particularly dichloromethane).

The reaction is conducted at a temperature of -50° to 100° C. The timerequired for the reaction varies mainly depending upon the reactiontemperature and the nature of the starting compound within a period of30 minutes to 15 hours. The oxidation reaction described above isaccelerated by adding a phase transfer catalyst such astriethylbenzylammonium chloride or tributylbenzylammonium bromide.

Step 38!

In this step an intermediate, mononucleotide (9) can be prepared byreacting a compound (2) with a phosphorylating agent, for example,bistriazolide in the presence of an inert solvent and adding waterfollowed by working-up.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. The solvent isnormally selected from aromatic amines such as pyridine. There is noparticular limitation upon the nature of V used in the definition of thephosphorylating agent, provided that it can be removed under thecondition removing a protecting group of a base moiety after completionof the condensation reaction of Step 39. V signifies usually ao-chlorophenoxy gorup.

Although the reaction temperature is not particularly critical, thereaction is carried out at a temperature of -20° to 100° C., normally atroom temperature. The time required for the reaction varies dependingupon the nature of the solvent used and the reaction temperature. Whenthe reaction is carried out at room temperature using pyridine as asolvent, it is complete within a period of an hour.

Step 39!

In this step the final product (1) can be prepared by condensing amononucleotide (9) with CPG-bound ODN (3, 4a, 4b, 5, 6a to 6d, 7a or7b), which is synthesized on a DNA synthesizer and deprotected a5'-terminal DMT group, having protecting groups in the base andphosphoric acid moieties by the use of a condensing agent to form aphosphoric acid triester group, cleaving from CPG by conventional means,deprotecting a protecting group, and finally purifying. There is noparticular limitation upon the nature of the solvent used, provided thatit has no adverse effect upon the reaction.

Examples of condensing agents include: dicyclocarbodiimide (DCC),mesitylenesulfonyl chloride (Ms-Cl), triisopropylbenzenesulfonylchloride, mesitylenesulfonyltriazole (MST),mesitylenesulfonyl-3-nitrotriazole (MSNT),triisopropylbenzenesulfonyltetrazole (TPS-Te),triisopropylbenzenesulfonylnitroimidazole (TPS-NI) andtriisopropylbenzenesulfonylpyridyltetrazole; preferably MSNT, TPS-Te andTPS-NI.

The reaction temperature is not particularly critical but the reactionis carried out at a temperature of -10° to 100° C., usually at roomtemperature. Although the time required for the reaction variesdepending upon the nature of the solvent used and the reactiontemperature. When the reaction is carried out at room temperature usingpyridine as a solvent, it is complete within a period of 30 minutes.

Cleaving ODN from CPG-bound ODN and removing the protecting groupsexcepting the 5'-terminal substituent are carried out according to themethods known per se (J. Am. Chem. Soc., 103, 3185(1981)!. The reactionmixture containing the compounds of general formula (1) is purified byconventional purification techniques, for example, variouschromatography including reverse phase and ion-exchenge chromatography(comprizing high speed liquid chromatography) to produce the compoundshaving the said general formula (1).

Step 40!

In this step tris(1,2,4-triazolyl)phosphite which is previously preparedfrom phosphorus trichloride and 1,2,4-triazole according to theprocedure reported by B. C. Freohler, P. G. Ng and M. D. Matteucci inNucleic Acids Res., 14, 5399(1986) is reacted with a compound (2) in aninert solvent and the reaction is stopped by adding water followed byworking-up to produce a nucleoside 3'-H-phosphonate (10). There is noparticular limitation upon the nature of the solvent used, provided thatit has no adverse effect upon the reaction. A preferred solvent is ahalogenated hydrocarbon such as dichloromethane. The reactiontemperature is not particularly critical but the reaction is carried outat a temperature of -20° to 100° C., usually at room temperature.

The time required for the reaction varies depending upon the nature ofthe solvent used and the reaction temperature. When the reaction iscarried out at room temperature using dichloromethane as a solvent, itis complete within a period of 30 minutes.

Step 41!

In this step the final product (1) can be prepared by reacting thenucleoside 3'-H-phosphonate (10) prepared in Step 40 with CPG-bound ODN(3, 4a, 4b, 5, 6a to 6d, 7a or 7b), which is synthesized on asynthesizer and deprotected a 5'-terminal DMT group alone, havingprotecting groups in the base and phosphoric acid moieties by the use ofa condensing agent such as pivaloyl chloride in the presence of adeacidifying agents to produce a H-phosphonic acid diester bond,transforming the H-phosphonic acid group to a phosphoric acid diestergroup using an oxidizing agent, cleaving ODN from CPG-bound ODN andconcurrently removing the protecting group of a base moiety under basicconditions, and finally purifying. There is no particular limitationupon the nature of the solvent used, provided that it has no adverseeffect upon the reaction. A preferred solvent is anhydrous acetonitrile.Examples of condensing agents include acid chlorides and phosphoricchloride, preferably pivaloyl chloride.

There is no particular limitation upon the nature of the oxidizing agentused for oxidizing a H-phosphonic acid group of ODN to a phosphoric aciddiester group, provided that it can be used as an oxidizing agent inoxidation reactions. Examples of suitable oxidizing agents include:inorganic metal oxides including manganese oxides such as potassiumpermanganate or manganese dioxide; ruthenium oxides such as rutheniumtetraoxide; selenium oxides such as selenium dioxide; iron compoundssuch as ferric chloride; osmium compounds such as osmium tetraoxide;silver compounds such as silver oxide; mercuryl compounds such asmercury acetate; lead oxide compounds such as lead oxide or leadtetraoxide; chromic acid compounds such as potassium chromate, a complexof chromic acid and sulfuric acid or a complex of chromic acid andpyridine; and cerium compounds such as cerium ammonium nitrate (CAN);inorganic oxidizing agents including halogen molecules such as achlorine, bromine or iodine molecule; periodides such as sodiumperiodide; ozone; hydrogen peroxide; nitrous compounds such as nitrousacid; chlorous acid compounds such as sodium chlorite; and persulfatecompounds such as potassium persulfate or sodium persulfate; and organicoxidizing agents including reagent used in DMSO oxidation (a combinationof dimethylsulfoxide and dicyclohexylcarbodiimide, oxalyl chloride,acetic anhydride or phosphorus pentachloride or a complex of pyridineand sulfuric anhydride); peroxides such as tert-butyl hydroperoxide;stable cations such as triphenylmethyl cation; succinimides such asN-bromosuccinimide; hypochlorous acid compounds such as tert-butylhypochlorite; azodicarboxylic acid compounds such as azodicarboxylate; acombination of disulfides such as dimethyl disulfide, diphenyl disulfideor dipyridyl disulfide and triphenylphosphine; nitrites such as methylnitrite; tetrahalogenated compounds such as tetrabromomethane; andquinone compounds such as 2,3-dichlor-5,6-dicyano-p-benzoquinone (DDQ);more preferably iodine.

As the deacidifying agent used there come into considerationheterocyclic amines such as pyridine or dimethylaminopyridine andaliphatic amines such as trimethylamine, triethylamine ordiisopropylethylamine; preferably aliphatic amines (particularlydiisopropylethylamine). The reaction temperature is not particularlycritical but the reaction is normally carried out at a temperature of-50° to 50° C., preferably at room temperature.

The time required for the reaction varies depending upon the nature ofthe starting compound and solvent used as well as the reactiontemperature, but the reaction is normally at a temperature of 5 minutesto 30 hours. When the reaction is carried out at room temperature, it ispreferably complete within a period of 30 minutes.

Cleaving ODN from CPG-bound ODN and removing the protecting groupsexcepting the 5'-terminal substituent are carried out according to themethods known per se (J. Am. Chem. Soc., 103, 3185(1981)).

The reaction mixture containing the compounds of general formula (1) ispurified by conventional purification techniques, for example, variouschromatography including reverse phase and ion-exchenge chromatography(comprizing high speed liquid chromatography) to produce the compoundshaving the said general formula (1).

The present invention further provides a new process for the synthesisof oligodeoxyribonucleotides and oligodeoxyribonucleotide derivatives.The new oligodeoxyribonucleotides of formula (11) prepared by the newprocess typically include the new compounds of the general formula (1).Furthermore, for use in the new process, the present invention providesnew intermediate compounds, as will be more concretely defined.

In the following description, a different set of definitions areemployed for the substituent groups, but the correspondence between therespective definitions may be readily recognized. Thus, for example, thesimilarity can be seen between the substituent group R₁ R₂ R₃ Z-- of thecompounds of general formula (1), and the substituent group R⁴ R⁵ R⁶ Z--shown for the compounds employed and produced by the new process.Moreover, it is necessary to note that the groups shown with subsciptidentifiers, such as R₁, R₂, Y₁, etc, are not always identical with thegroups shown with superscript identifiers, such as R¹, R², Y¹, etc.

In this aspect of the invention, the process provided by the inventioninvolves producing an oligodeoxyribonucleotide having a substitutedphosphate at the 3'-end. More particularly, the present inventionprovides novel linker compounds for use with polymer supports in thepreparation of solid phase materials for synthesis ofoligodeoxyribonucleotides. The solid phase materials can have aprotected hydroxy group at the end of the linker to the polymer support,which can then be deprotected and reacted to add nucleotides.

Thus, for example, the present invention provides linker compounds suchas the following compounds (12) which with polymer supports can giveprotected solid phase materials (14) for deprotection to compounds (22)and subsequent reaction to compounds (24), (25) and (27) with addednucleotides.

In one aspect, the present process is for producing a compoundrepresented by the formula (11): ##STR14## wherein R⁴, R⁵, R⁶ and agroup Z (wherein R⁴, R⁵ and R⁶ may be the same or different from oneanother and each independently represent a hydrogen atom, an alkyl grouphaving 1 to 4 carbon atoms, an optionally substituted aryl group or anoptionally substituted anthraquinonyl group; Z represents a carbon orsilicon atom; R⁵, R⁶ and Z may together represent a fluorenyl group or axanthenyl group; or R⁴, R⁵, R⁶ and Z may together represent a hydrogenatom); R⁷ represents a hydrogen atom, an optionally substituted alkylgroup having 1 to 4 carbon atoms, an optionally substituted aryl groupor an optionally substituted aralkyl group; Y² may be the same ordifferent and represents an oxygen atom, a sulfur atom or an NH group;Y³ represents an oxygen atom, a sulfur atom, an N group, an alkylenegroup having 1 to 4 carbon atoms or a phenylene group; X³ represents anoxygen or sulfur atom; and D represents an oligodeoxyribonucleotidehaving a chain length of 2 to 30, provided that the hydroxyl groups atthe 5'- and 3'-terminals are not included in D.!;

said process comprises:

reacting a compound represented by the formula (12): ##STR15## whereinR¹, R² and R³ may be the same or different from one another and eachindependently represent a hydrogen atom or an alkoxy group having 1 to 4carbon atoms; X¹ represents a group --S--, --SO-- or --SO₂ ; Arepresents a group --(CH₂)_(h) -- (wherein h is an integer of 1 to 16),a group --(CH₂)_(h) O-- (wherein h is an integer of 1 to 16), a group--(CH₂)_(j) --O--CO--(CH₂)_(k) -- (wherein j is a positive integer, k is0 or a positive integer, and j+k is 2 to 16) or a group --(CH₂)_(j)--NH--CO--(CH₂)_(k) -- (wherein j is a positive integer, k is 0 or apositive integer, and j+k is 2 to 16), a group --(CH₂)_(j)--S--CO--(CH₂)_(k) -- (wherein j is a positive integer, k is 0 or apositive integer, and j+k is 2 to 16) or a group --(CH₂)_(n)--O--CO--CH₂ (OCH₂ CH₂)_(p) --OCH₂ -- (wherein n is a positive integer,p is 0 or a positive integer, and j+k is 2 to 100); and Y¹ represents ahydroxyl group, an optionally substituted phenyloxy group or an ethyloxygroup which may be substituted by a halogen.!

with a polymeric material represented by the general formula (13):##STR16## wherein X² represents an oxygen atom, a sulfur atom or an NHgroup; and P represents a polymeric material.! (provided that in thecase where Y¹ in the general formula (12) is a hydroxyl group, thecompound of the general formula (12) is reacted with a carboxylic acidactivating agent before reaction with the polymeric material (13)) toform a polymeric material represented by the general formula (14):##STR17## wherein R¹, R², R³, X¹, A, X² and P have the same meanings asdefined above; and

subjecting the resulting polymeric material of the formula (14) to DNAchain extension treatment using a DNA synthesizer.

This process of the present invention is shown in the following flowcharts. ##STR18##

In the above flow charts, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X¹, X², X³, P, Y¹,Y², Y³, A and Z have the same meanings as defined above (however, in thecompounds other than the compound (11), R⁴, R⁵, R⁶ and Z together do notrepresent a hydrogen atom). R^(8a) represents a methyl group or acyanoethyl group; R^(8b) represents a phenyl group optionallysubstituted by a chloro group; R⁸ represents a methyl group, acyanoethyl group or a phenyl group optionally substituted by a chlorogroup; R^(9a) represents a hydrogen atom or a hydrogen group having aprotecting group; X represents a halogen atom (preferably chlorine,bromine and iodine); A¹ represents an alkylene group having 1 to 20carbon atoms; m is an integer of 1 to 14; n is an integer of 1 to 28; B,B' and B" each represent the base moiety of adenine nucleotide, guaninenucleotide, thymine nucleotide, uracil nucleotide and cytosinenucleotide protected at the base and phosphate moieties (they should beselected to provide a desired base sequence); with the provide that B'represents the base moiety of the 3'-terminal nucleotide of D having thedesired base sequence; B" represents the base moiety of the 5'-terminalnucleotide of D having the desired base sequence; D represents thedesired oligodeoxyribonucleotide (provided that the 5'-terminal hydroxylgroup and the 3'-terminal hydroxyl group are not included); Q representsa halogenoalkyl group, a halogenophenyl group or a nitrophenyl groupsuch as a 2,2,2-trichloroethyl group, 2,2-dichloroethyl group,2-chloroethyl group, 2,2,2-tribromoethyl group, 2,2-dibromoethyl group,2-bromoethyl group, 2-nitrophenyl group, 4-nitrophenyl group,2,4-dinitrophenyl group, 2,4,5-trichlorophenyl group and2,3,4,5,6-pentachlorophenyl group (preferably trichloroethyl group andorthonitrophenyl group); V represents a lower alkyl group (preferablymethyl, ethyl and isopropyl groups, particularly isopropyl group).

Next, each step will be described in detail.

(Step 1)

This step is for preparing a compound (17) by reacting 2-mercaptoethanol(16) with a ω-halogenocarboxylic acid (15) in an inert solvent in thepresence of an acid binding agent.

The solvent employable is not particularly limited unless it affects thereaction, and it includes aromatic hydrocarbons such as benzene, tolueneand xylene; halogenated hydrocarbons such as methylene chloride andchloroform; ethers such as ether, tetrahydrofuran, dioxane anddimethoxyethane; amides such as dimethylformamide, dimethylacetamide andhexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol and isoamyl alcohol; dilute acids such as aqueous sulfuricacid; dulute bases such as aqueous sodium hydroxide; water; ketones suchas acetone, methyl ethyl ketone; heterocyclic amines such as pyridine;and nitriles such as acetonitrile, preferably ketones such as acetoneand alcohols such as ethanol and propanol.

The acid binding agent employable includes alkali metal carbonates suchas potassium carbonate and sodium carbonate; alkali metalhydrogencarbonates such as sodium hydrogencarbonate; alkali metalhydroxides such as sodium hydroxide and potassium hydroxide; and organicamines such as triethylamine, preferably alkali metal carbonates(particularly potassium carbonate).

Reaction temperature and reaction time vary depending on the solvent,acid binding agent, etc. employed, the reaction is carried out underreflux with heating for 8 hours when potassium carbonate is used.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

(Step 2)

This step is for preparing a compound (18), which corresponds to thecompound (17) whose hydroxyl group is protected, by reacting thecompound (17) with a protecting reagent, which can be eliminated(preferably dimethoxytrityl chloride) under an acidic condition in aninert solvent in the presence of an acid binding agent.

The solvent employable is not particularly limited so long as it doesnot affect the reaction and can dissolve the starting materials to acertain degree, and it includes aromatic hydrocarbons such as benzene,toluene and xylene; halogenated hydrocarbons such as methylene chlorideand chloroform; ethers such as ether, tetrahydrofuran, dioxane anddimethoxyethane; amides such as dimethylformamide, dimethylacetamide andhexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide;ketones such as acetone, methyl ethyl ketone; heterocyclic amines suchas pyridine; and nitrites such as acetonitrile, preferably heterocyclicamines (especially pyridine).

The protecting reagent employable includes trityl halides such as tritylchloride, monomethoxytrityl chloride, dimethoxytrityl chloride andtrimethoxytrityl chloride, preferably dimethoxytrityl chloride.

The acid binding agent employable is not particularly limited unless itaffects the reaction and decomposes the product and the startingmaterials, and it preferably includes aromatic amines such as pyridineand dimethylaminopyridine.

While reaction temperature and reaction time vary depending on the kindof the protecting reagent and acid binding agent employed, the reactionis carried out at room temperature for 2 hours when dimethoxytritylchloride is used as a protecting reagent and pyridine is used as asolvent and also as an acid binding agent.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

(Step 3)

This step is for preparing the compound (18) by reacting a compound (19)with a dicarboxylic anhydride (20) in an inert solvent.

The solvent employable is not particularly limited so long as it doesnot affect the reaction and can dissolve the starting materials to acertain degree, and it includes aromatic hydrocarbons such as benzene,toluene and xylene; halogenated hydrocarbons such as methylene chlorideand chloroform; ethers such as ether, tetrahydrofuran, dioxane anddimethoxyethane; amides such as dimethylformamide, dimethylacetamide andhexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide;ketones such as acetone, methyl ethyl ketone; heterocyclicamines such as pyridine and nitriles such as acetonitrile, preferablyhalogenated hydrocarbons such as methylene chloride.

The acid binding agent employable includes pyridines such as pyridine,dimethylaminopyridine and 4-pyrrolidinopyridine, preferablydimethylaminopyridine.

While the dicarboxylic anhydride employable is not particularly limitedso long as it is anhydrides of α,ω-alkyldicarboxylic acid having 3 to 16carbon atoms, it is preferably succinic anhydrides.

While reaction temperature and reaction time vary depending on the kindof the acid anhydride, acid binding agent, etc. employed, the reactionis carried out at room temperature for 30 minutes when succinicanhydride is used and dimethylaminopyridine is used as an acid bindingagent.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

(Step 4)

This step is for forming an active ester (12) by reacting the carboxylgroup of the compound (18) having a free carboxyl group with an esterforming reagent, followed by reaction with an optionally substitutedphenol.

The solvent employable is not particularly limited unless it affects thereaction, and it includes aromatic hydrocarbons such as benzene, tolueneand xylene, halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene anddichlorobenzene; esters such as ethyl formate, ethyl acetate, propylacetate, butyl acetate and diethyl carbonate; ketones such as acetone,methyl ethyl ketone methyl isobutyl ketone, isophorone andcyclohexanone; nitro compounds such as nitroethane and nitrobenzene;nitriles such as acetonitrile and isobutyronitrile; amides such asformamide, dimethylformamide (DMF), dimethylacetamide andhexamethylphosphorotriamide; and sulfoxides such as dimethyl sulfoxideand sulforane, preferably halogenated hydrocarbons (particularlymethylene chloride) and amides (particularly dimethylformamide).

The phenol employable is not particularly limited so long as it can beused as an active ester, and it includes 4-nitrophenol,2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol and2,3,5,6-tetrafluorophenol, preferably pentachlorophenol.

The ester forming reagent employable includes, for example, N-hydroxycompounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole andN-hydroxy-5-norbornene-2,3-dicarboxyimide; diimidazole compounds such as1,1'-oxalyldiimidazole and N,N'-carbonyldiimidazole; disulfide compoundssuch as 2,2'-dipyridyldisulfide; succinic acid compounds such asN,N'-disuccinimidyl carbonate; phosphinic chloride compounds such asN,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride; oxalate compoundssuch as N,N'-disuccinimidyl oxalate (DSO), N,N-diphthalimidyl oxalate(DPO), N,N'-bis(norbornenylsuccinimidyl) oxalate (BNO),1,1'-bis(benzotriazolyl) oxalate (BBTO),1,1'-bis(6-chlorobenzotriazolyl) oxalate (BCTO) and1,1'-bis(6-trifluoromethylbenzotriazolyl) oxalate (BTBO); andcarbodiimides such as dicyclohexylcarbodiimide (DCC), preferablydiimidazole compounds and carbodiimides (particularly DCC).

While reaction temperature and reaction time vary depending on the kindof the ester forming reagent and solvent employed, the reaction iscarried out at 0° C. to 100° C. for 5 to 50 hours, and particularly whenpentachlorophenol and DCC are used in DMF, the reaction is carried outat room temperature for 18 hours.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

(Step 5)

This step is for preparing a compound (12) by reacting the compound (19)with a compound (21) in an inert solvent in the presence of an acidbinding agent.

The solvent employable is not particularly limited unless it affects thereaction, and it includes aromatic hydrocarbons such as benzene, tolueneand xylene; halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene anddichlorobenzene; esters such as ethyl formate, ethyl acetate., propylacetate, butyl acetate and diethyl carbonate; ketones such as acetone,methyl ethyl ketone, methyl isobutyl ketone, isophorone andcyclohexanone; nitro compounds such as nitroethane and nitrobenzene;nitriles such as acetonitrile and isobutyronitrile; amides such asformamide, dimethylformamide (DMF), dimethylacetamide andhexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide andsulforane, preferably halogenated hydrocarbons, particularly methylenechloride.

The acid binding agent employable includes organic bases such astriethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazabicyclo 4.3.0!non-5-ene, 1,4-diazabicyclo2.2.2!octane (DABCO) and 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU),preferably organic bases, particularly pyridine and N-methylmorpholine.

While reaction temperature and reaction time vary depending on the kindof the acid binding agent employed, the reaction is usually carried outat 10° C. to 40 ° C. for 1 to 5 hours.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

(Step 6)

This step is for preparing a polymer derivative (14) employable as thecarrier for synthesizing an oligonucleotide by reacting the compound(12) having an activated carboxyl group obtained in Step 5 with apolymeric material (13) such as controlled pore glass (CPG) to which anamino group, a hydroxyl group, a sulfhydryl group, etc. are bound via analkylene group in an inert solvent.

While the polymeric material (13) employable in this step is notparticularly limited so long as it can usually be used as a carrier, theparticle size, the surface area of three-dimentional reticulatestructure; the proportion of hydrophilic group site, chemicalcomposition, pressure resistance, etc. of the carrier should beexamined.

The carrier employable includes polysaccharide derivatives such ascellulose, dextran and agarose, synthetic polymers such aspolyacrylamide gel, polystyrene resins and polyethylene glycol, andinorganic materials such as silica gel, porous glass and metal oxides,typified nonlimitatively by commercially available carriers such asAminopropyl-CPG and Long-chain aminoalkyl-CPG (manufactured by CPGInc.); Cosmosil NH₂ and Cosmosil Diol (manufactured by Nakarai Tesuku);CPC-Silica Carrier Silane Coated, Aminopropyl-CPG-550A,Aminopropyl-CPG-1400A and polyethylene glycol 5000 monomethyl ether(manufactured by Furuka Co.), p-alkoxybenzyl alcohol resin, aminomethylresin and hydroxymethyl resin (manufactured by Kokusan Kagaku K. K.);and polyethylene glycol 14000 monomethyl ether (manufactured by UnionCarbide).

Further, the functional group bonded to the carrier preferably includesan amino group, a sulfhydryl group and hydroxyl group.

The solvent employable is not particularly limited so long as it doesnot affect the reaction and can dissolve the starting materials to someextent, and it preferably includes aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate and diethyl carbonate; ketonessuch as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds such as nitroethane and nitrobenzene;nitriles such as acetonitrile and isobutyronitrile; amides such asformamide, dimethylformamide, dimethylacetamide andhexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide andsulforane, preferably halogenated hydrocarbons (particularly methylenechloride) and amides (particularly dimethylformamide).

Reaction temperature is usually from -20° to 150° C., preferably from 0°to 50° C.

While reaction time varies depending on the starting materials, solvent,reaction temperature employed, it is usually 1 to 200 hours, preferably24 to 100 hours.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, the desirable polymeric carrier is recovered by filtrationfrom the reaction mixture, washed with an organic solvent such asmethylene chloride and dried under reduced pressure to give the desiredcompound.

(Step 7)

This step is for preparing a compound (22) by reacting the compound (14)with a deprotecting reagent in an inert solvent to eliminate selectivelythe protecting group of the hydroxyl group.

Incidentally, Step 7 to Step 11 are usually performed in a DNAsynthesizer.

The solvent employable preferably includes aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethylacetate, propyl acetate, butyl acetate and diethyl carbonate; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane and diethylene glycol dimethyl ether; alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol,cyclohexanol and methyl cellosolve; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone;nitro compounds such as nitroethane and nitrobenzene; nitriles such asacetonitrile and isobutyronitrile; amides such as formamide,dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide;sulfoxides such as dimethyl sulfoxide and sulforane, more preferablyalcohols (particularly methanol and ethanol) and methylene chloride, andwhen acetic acid is used as a deprotecting reagent, a mixture of aceticacid and water is included.

While the deprotecting reagent employable is not particularly limited solong as it is customarily used, and if the protecting group is atriarylmethyl group, acetic acid, dichloroacetic acid, trifluoroaceticacid, hydrochloric acid and a Lewis acid such as zinc bromide areexemplified, preferably acetic aced, dichloroacetic acid andtrilfuoroacetic acid can be used.

While reaction temperature varies depending on the reagent, startingmaterials and solvent employed, it is usually from -10° to 100° C.,preferably from 0° to 50° C.

While reaction time varies depending on the starting materials, solventand reaction temperature employed, it is usually from 1 minute to 50hours, preferably from 1 minute to 24 hours.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, the polymeric carrier is recovered by filtration from thereaction mixture, washed with an organic solvent such as methylenechloride and dried under reduced pressure to give the desired compound.

(Step 8)

This step is for preparing a compound (24) by reacting a compound (23),(23') or (23") having a dimethoxytrityl group at the 5'-hydroxyl group,in which the base moiety is that of the 3' terminal of a desirable basesequence, and the 3'-hydroxyl group has, via phosphorus bonded thereto adesired alkyloxy, phenyloxy, aralkyloxy, alkyl, aralkyl or phenyl groupwith the polymeric material (22), followed by thioation oralkylamination, if necessary, to give such compound (24) having thedesired 3'-terminal nucleotide unit bonded to a polymeric material suchas CPG.

The compounds (23), (23') and (23") employable will be described below,respectively.

(a) If the compound (23) is reacted in this step, an acidic material isemployed.

The acidic material employable includes those such as tetrazole etc.,preferably tetrazole. While the oxidizing agent employable in theoxidation reaction in this step is not particularly limited so long asit is usually used in oxydation reactions, it preferably includesinorganic metal oxidizing agents such as manganese oxides, e.g.potassium permanganate and manganese dioxide; ruthenium oxides, e.g.ruthenium tetroxide; selenium compounds, e.g. selenium dioxide; ironcompounds, e.g. iron(III) chloride; osmium compounds, e.g. osmiumtetroxide; silver compounds, e.g. silver oxide; mercury compounds, e.g.mercury acetate; lead oxide compounds, e.g. lead oxide and leadtetroxide; chromic acid compounds, e.g. potassium chromate, chromicacid-sulfuric acid complex and chromic acid-pyridine complex; and ceriumcompounds e.g. cerium ammonium nitrate (CAN); inorganic oxidizing agentssuch as halogen molecules, e.g. chlorine molecules bromine molecule andiodine molecule; periodic acids, e.g. sodium periodate; ozone, aqueoushydrogen proxide; nitrous acid compounds, e.g. nitrous acid; chlorousacid compounds, e.g. potassium chlorite and sodium chlorite; andpersulfuric acid compounds, e.g. potassium persulfate and sodiumpersulfate; and organic oxidizing agents such as reagents employable forDMSO oxidation (a complex of dimethyl sulfoxide anddicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride orphosphorus pentoxide or a complex of pyridine-sulfuric anhydride);peroxides, e.g. t-butyl hydroperoxide; stable cations, e.g.triphenylmethyl cation; succinimides, e.g. N-bromosuccinimide,hypochlorous acid compounds, e.g. t-butyl hypochlorite; azodicarboxylicacid compounds, e.g. azodicarboxylic acid ester; disulfides, e.g.dimethyl disuslfide, diphenyl disulfide and dipyridyl disulfide andtriphenylphosphine; nitrous acid esters, e.g. methyl nitrite; carbontetrahalides, e.g. methane tetrabromide, and quinone compounds, e.g.2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably iodo. Thesolvent employable is not particularly limited so long as it does notaffect the reaction and can dissolve the starting materials to someextent, and it includes aromatic hydrocarbons such as benzene, tolueneand xylene; halogenated hydrocarbons such as methylene chloride andchloroform; ethers such as ether, tetrahydrofuran, dioxane anddimethoxyethane; amides such as dimethylformamide, dimethylacetamide andhexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide;ketones such as acetone, methyl ethyl ketone; heterocyclic amines suchas pyridine; and nitrites such as acetonitrile, preferably heterocyclicamines (particularly pyridine), nitriles (particularly acetonitrile),ethers (particularly tetrahydrofuran) and halogenated hydrocarbons(particularly methylene chloride).

Reaction is carried out at -50° to 100° C., and while reaction timevaries depending mainly on the reaction temperature, types of thestarting compounds and solvent employed, it is usually 5 minutes to 15hours.

(b) The solvent employed when the compound (23') is reacted is notparticularly limited unless it affects the reaction, and an aromaticamine such as pyridine is preferably used.

In the case where the compound (23') is reacted, a condensation agent isusually used.

The condensation agent employable includes dicyclocarbodiimide (DCC),mesitylenesulfonic acid chloride (Ms-Cl), triisopropylbenzenesulfonicacid chloride, mesitylenesulfonic acid triazolide (MST),mesitylenesulfonic acid-3-nitrotriazolide (MSNT),triisopropylbenzenesulfonic acid tetrazolide (TPS-Te),triisopropylbenzenesulfonic acid nitroimidazolide (TPS-NI) andtriisopropylbenzenesulfonic acid pyridyltetrazolide, preferably MSNT,TPS-Te and TPS-NI. While reaction temperature is not particularlylimited in the range of -10° to 100° C., the reaction is usually carriedout at room temperature. While the reaction time varies depending on thesolvent and reaction temperature employed, it is 30 minutes in the casewhere the reaction is carried out at room temperature using pyridine asthe solvent for the reaction.

(c) While the solvent employable when the compound (23") is reacted isnot particularly limited unless it affects the reaction, anhydrousacetonitrile is preferably used. As the reagent used as the condensationagent, acid chlorides of carboxylic acid and phosphoric acid are used,and preferably pivaloyl chloride is used.

While the oxidizing agent for oxidizing an oligonucleotide having aH-phosphonate bond to a phosphodiester type-oligonucleotide is notparticularly limited so long as it is usually used for oxidationreactions, it preferably includes inorganic metal oxidizing agents suchas manganese oxides, e.g. potassium permanganate and manganese dioxide;ruthenium oxides, e.g. ruthenium tetroxide; selenium compounds, e.g.selenium dioxide; iron compounds, e.g. iron(III) chloride; osmiumcompounds, e.g. osmium tetroxide; silver compounds, e.g. silver oxide;mercury compounds, e.g. mercury acetate; lead oxide compounds, e.g. leadoxide and lead tetroxide; chromic acid compounds, e.g. potassiumchromate, chromic acid-sulfuric acid complex and chromic acid-pyridinecomplex; and cerium compounds e.g. cerium ammonium nitrate (CAN);inorganic oxidizing agents such as halogen molecules, e.g. chlorinemolecule, bromine molecule and iodine molecule; periodic acids, e.g.sodium periodate; ozone; aqueous hydrogen proxide; nitrous acidcompounds such as nitrous acid; chlorous acid compounds, e.g. potassiumchlorite and sodium chlorite; and persulfuric acid compounds, e.g.potassium persulfate and sodium persulfate; and organic oxidizing agentssuch as reagents employable for DMSO oxidation (a complex of dimethylsulfoxide and dicyclohexylcarbodiimide, oxalyl chloride, aceticanhydride or phosphorus pentoxide or a complex of pyridine-sulfuricanhydride); peroxides, e.g. t-butyl hydroperoxide; stable cations, e.g.triphenylmethyl cation; succinimides, e.g. N-bromosuccinimide,hypochlorous acid compounds, e.g. t-butyl hypochlorite; azodicarboxylicacid compounds, e.g. methyl azodicarboxylate; disulfides, e.g. dimethyldisuslfide, diphenyl disulfide and dipyridyl disulfide andtriphenylphosphine; nitrous acid esters, e.g. methyl nitrite; carbontetrahalides, e.g. methane tetrabromide, and quinone compounds, e.g.2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably iodinemolecule.

The acid binding agent employable includes heterocyclic amines such aspyridine and diemthylaminopyridine, and aliphatic amines such astrimethylamine, triethylamine and diisopropylethylamine, preferablyheterocyclic amines (particularly pyridine). While reaction temperatureis not particularly limited, it is usually -50° to 50° C., preferablyroom temperature.

While reaction time varies depending on the starting materials, reagent,temperature, etc. employed, it is usually 5 minutes to 30 hours,preferably 30 minutes when the reaction is carried out at roomtemperature.

The thioation which is carried out, if desired, in this step isperformed as follows: After the compound (23) is bonded to the compound(22), a thioation reagent is reacted to effect thioation in place of theoxidation with an iodine molecule etc. to give a compound (24) which isa polymeric carrier having a thioate bond such as CPG.

The reagent for thioation is not particularly limited so long as it canform a thioate by reaction with trivalent phosphorous, and it preferablyincludes sulfur and also tetraethyl thiurum disulfide (TETD) availablefrom Applied Biosystems and Beaucage reagent available fromMilliGen/Biosearch. In the case of using the former, the processdescribed in a known literature (Tetrahedron Letters, 32, 3005 (1991) orits variations, and in the case of the latter, the process disclosed ina known literature (J. Am. Chem. Soc. 112, 1253 (1990) or its variationscan nonlimitatively be used.

The alkylamination carried out, if desired, in this step can beperformed as follows: After the compound (23") is bonded to the compound(22) as described above, a desired alkylamine is reacted therewith atroom temperature in place of the oxidizing agent such as an iodinemolecule. According to this process, a compound (24), in which the3'-terminal nucleotide having the desired base sequence is bonded with apolymeric material such as CPG through phosphoramidate bond, can beobtained.

(Step 9)

This step is carried out by 1) treating the polymeric material (24)obtained in Step 8 with an acid to eliminate the DMT group, 2) reactingthe thus treated polymeric material with an amidite reagent and an acidcatalyst, 3) subjecting the resulting material to an oxidation reactionusing an oxidizing agent and 4) subjecting the unreacted moiety to acapping reaction using acetic anhydride. In this step, the aboveprocedures 1) to 4) are repeated to obtain a compound (25) to which onlythe 5'-terminal nucleotide having the desired base sequence is not yetbonded. The extension reaction of the DNA chain on a DNA synthesizeremployed in this step is performed, for example, by a variation of themethod of Stec (J. Am. Chem. Soc., 106, 6077-6089 (1984)) using thephosphoroamidite method using Applied Biosystems Model 380B or thephosphoroamidite method (method of H. Koester et al., in Nucleic AcidsRes., 12, 4539 (1984)) using the Cyclone Plus DNA synthesizer ofMilliGen/Biosearch, but the method is not limited thereto.

(Step 10)

This step is for preparing a polymeric material (27) having the desiredbase sequence and substituents, and also retaining a protecting group byeliminating the 5'-terminal DMT group of the polymeric material (25)obtained in Step 9 according to the procedures in Step 7, followed bythe same treatment as in Step 8 using compounds (26), (26') and (26"),as described below, in place of the compounds (23), (23') and (23").

The compounds (26), (26') and (26") each are 2'-deoxyribonucleosidehaving a base moiety in which the 5'-terminal nucleotide of the desiredbase sequence is protected, or a ribonucleoside having a protectedhydroxyl group at the 2'-position, with a desired modifying group at the5'-position. Further, the compound (26) has at the 3'-position thereof aphosphoroamidite bond including the protecting group of the phosphatemoiety to be used for ordinary DNA synthesis. Likewise, the compound(26') has a phosphodiester bond, and the compound (26") has aH-phosphonate bond.

(Step 11)

This step is for preparing a desired oligonucleotide (11) by cleavingthe oligonucleotide portion from the polymeric material (27), carried onthe protected polymeric material obtained in Step 10, has the desiredbase sequence and substituents at the 5'- and 3'-terminals, andeliminating the protecting groups other than the desired substituents atthe 5'-terminal and/or 3'-terminal. The elimination of the protectinggroup can be carried out by known procedures (J. Am. Chem. Soc., 103,3185(1981)).

The thus obtained reaction mixture containing the compound of thegeneral formula (11) is purified by means of an ordinary purificationtreatment employable for purification of nucleic acid, for example,various chromatographies such as reverse phase and/or ion exchangechromatography (including high performance liquid chromatography), etc.to give the compound having the general formula (11).

(Step 12)

This step is for preparing a half ester of dicarboxylic acid, i.e. thecompound (15) which is the starting material of the present invention byreacting the free hydroxyl group of a compound (29) or the freesulfhydryl group of a compound (30) with a dicarboxylic anhydride like acompound (28) in an inert solvent in the presence of a basic catalyst.

The dicarboxylic anhydride employable is not particularly limited andpreferably includes dicarboxylic anhydrides having 1 to 16 carbon atoms,and most preferably succinic anhydride or glutaric anhydride. The basiccatalyst employable includes preferably aminopyridines such asdimethylaminopyridine and pyrrolidinopyridine, tertiary amines such astrimethylamine and triethylamine, and carbonates of alkali metals suchas sodium hydrogencarbonate and potassium carbonate, most preferablydimethylaminopyridine and pyrrolidinopyridine.

The solvent employable is not particularly limited so long as it doesnot affect the reaction and can dissolve the starting materials to someextent, and it preferably includes aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such as methylenechloride and chloroform; ethers such as ether, tetrahydrofuran, dioxaneand dimethoxyethane; amides such as dimethylformamide, dimethylacetamideand hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide;alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol and isoamyl alcohol; dilute acids such as aqueous sulfuricacid; dilute bases such as aqueous sodium hydroxide; water; ketones suchas acetone, methyl ethyl ketone; heterocyclic amines such as pyridineand nitriles such as acetonitrile, preferably nitriles (particularlyacetonitrile), ethers (particularly tetrahydrofuran) and halogenatedhydrocarbons (particularly methylene chloride).

The reaction is carried out at -50° to 100° C., and while reaction timevaries depending on the reaction temperature, the kind of startingmaterials and solvent employed, it is usually 30 minutes to 15 hours.

After completion of the reaction, the desired compound is collected fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

(Step 13)

This step is for preparing a compound (18) by reacting compound (19)with dicarboxylic acid (31) in an inert solvent in the presence of anester forming reagent.

The solvent employable is not particularly limited unless it affects thereaction, and it includes aromatic hydrocarbons such as benzene, tolueneand xylene; halogenated hydrocarbons such as methylene chloride,chloroform, carbon-tetrachloride, dichloroethane, chlorobenzene anddichlorobenzene; esters such as ethyl formate, ethyl acetate, propylacetate, butyl acetate and diethyl carbonate; ketones such as acetone,methyl ethyl ketone methyl isobutyl ketone, isophorone andcyclohexanone; nitro compounds such as nitroethane and nitrobenzene;nitriles such as acetonitrile and isobutyronitrile; amides such asformamide, dimethylformamide (DMF), dimethylacetamide andhexamethylphosphorotriamide; and sulfoxides such as dimethyl sulfoxideand sulforane, preferably halogenated hydrocarbons (particularlymethylene chloride) and amides (particularly dimethylformamide).

The ester forming reagent employable includes, for example, N-hydroxycompounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole andN-hydroxy-5-norbornene-2,3-dicarboxyimide; diimidazole compounds such as1,1'-oxalyldiimidazole and N,N'-carbonyldiimidazole; disulfide compoundssuch as 2,2'-dipyridyldisulfide; succinic acid compounds such asN,N'-disuccinimidyl carbonate; phosphinic chloride compounds such asN,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride; oxalate compoundssuch as N,N'-disuccinimidyl oxalate (DSO), N,N-diphthalimidyl oxalate(DPO), N,N'-bis(norbornenylsuccinimidyl) oxalate (BNO),1,1'-bis(benzotriazolyl) oxalate (BBTO),1,1'-bis(6-chlorobenzotriazolyl) oxalate (BCTO) and1,1'-bis(6-trifluoromethylbenzotriazolyl) oxalate (BTBO); andcarbodiimides such as dicyclohexylcarbodiimide (DCC), preferablydiimidazole compounds and carbodiimides (particularly DCC).

While reaction temperature and reaction time vary depending on the kindof the ester forming reagent and solvent employed, the reaction iscarried out at 0° C. to 100° C. for 5 to 50 hours.

After completion of the reaction, the desired compound is isolated fromthe reaction mixture by conventional procedures.

For example, after the reaction mixture is appropriately neutralized andthe insolubles, if present, are removed by filtration, awater-immiscible organic solvent such as ethyl acetate is added to thereaction mixture. After the resulting mixture is washed with water, theorganic layer containing the desired compound is separated and driedover anhydrous magnesium sulfate, followed by evaporation of the solventto give the desired compound.

The desired compound thus obtained may further be purified byconventional procedures such as recrystallization, reprecipitation,chromatography, etc., if necessary.

According to the new process of the present invention, a modifiedoligonucleotide having a desired substituent at the 3'-terminal of theoligonucleotide via phosphate can easily be synthesized on a DNAsynthesizer, thus providing modified oligonucleotide with high purity ina large amount using simple purification procedures at a low cost.Useful oligonucleotides having a substituent at the 3'-terminal aredescribed in Japanese Patent Application No. Hei-301744, which hasanti-AIDS activities.

The compounds of the present invention exhibit a specific cytopathicactivity against AIDS virus (HIV-1) and can specifically inhibit theproliferation of the virus in infected cells. Accordingly the inventivecompounds may be used for the treatment and prevention of AIDS.

The present invention is concretely explained by illustration of thefollowing Examples.

TEST EXAMPLE 1! Measurement of Anti-HIV-1 Activity of ModifiedOligodeoxyribonucleotides

Anti-HIV-1 activity was measured by the method of Pawel et al. (R. Pauelet al., J. Virological Methods, 20, 309-321(1988)). In summary, MT-4cells in the exponential growth phase were centrifuged for 5 minutes at150×g. The cell pellet obtained was suspended in culture media andinfected with HIV-1 (Type IIIB) for 1 hour at 37° C. at a concentrationof 10 CCID₅₀. HIV-1 infected MT-4 cells were obtained by centrifugationin RPMI-1640 culture media containing 10% fetal calf serum (hereafter"serum culture media").

HIV-1 infected MT-4 cells and non-HIV-1 infected MT-4 cells weresuspended in serum culture media so that a concentration of 4×10cells/ml of each was attained. One hundred μl of a solution of stepwisediluted sample compound (dissolved in serum culture media), prepared inadvance, was placed in each well of 98-well microtiter plates. Then, 100μl of each of the above-mentioned cell suspensions was added to eachwell of microtiter plates, and their cells were cultured for 6 days inthe presence of 5% carbon dioxide gas.

As a control, HIV-1 infected MT-4 cells and non-HIV-1 infected MT-4cells in which no sample compound was added were cultured in the samemanner.

After the cultivation, live cell number was measured based on theMTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide)method (L. M. Green et al., J. Immunol, Methods, 70, 257-268(1984)).Then the cytopathic activity of HIV-1 was measured. With the cytopathicactivity of HIV-1 infected MT-4 cells to which no sample compound wasadded as 100%, and the cytopathic activity of non-HIV-1 (Type IIIB)infected MT-4 cells to which no sample compound was added as 0%, theconcentration of the specimen which inhibited the cytopathic activity ofHIV-1 infected MT-4 cells by 50(IC₅₀) was calculated. The cytotoxicityof the sample compound was determined as that concentration whichinhibited the multiplication of non-HIV-1 infected MT-4 cells by 50%(CC₅₀). The results of these measurements are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Example No    IC.sub.50 (μg/mol)                                                                    CC.sub.50 (μg/ml)                                 ______________________________________                                         1            2.1        61                                                   2             5.9        >100.0                                               4             1.5        >100.0                                               5             2.3        >100.0                                               6             1.3        >100.0                                               7             1.0        >100.0                                               8             4.3        >100.0                                               9             8.4        >100.0                                               10            1.5        >100.0                                               11            4.7        >100.0                                               12            0.6        >100.0                                               13            1.4        >100.0                                               14            0.7        >100.0                                               16            4.7        >100.0                                               17            3.7        >100.0                                               18            4.7        >100.0                                               19             6.25      >100.0                                               20            4.0        >100.0                                               21            1.2        100.0                                                22             0.55      50                                                   23            0.8        75                                                   24             0.45      75                                                   25            4.0        >100.0                                               26            6.0        80.0                                                 27            5.0        95.0                                                 28            5.0        >100.0                                               29            3.0        >100.0                                               30            1.0        >100.0                                               31            1.1        90.0                                                 32            3.8        >100.0                                               33            5.0        >100.0                                               34            5.0        >100.0                                               35            5.5        >100.0                                               36            1.5        100.0                                                37            6.0        >100.0                                               43            3.0        100.0                                                45             0.45      >100.0                                               48             0.58      >100.0                                               57            1.5        100.0                                                58            7.0        50.0                                                 70            1.0        60.0                                                 71            1.0        37.0                                                 72            1.8        >100.0                                               73            3.0        >100.0                                               74            4.4        >100.0                                               75            6.0        40.0                                                 76            7.0        >100.0                                               77            9.0        >100.0                                               78            9.0        >50.0                                                79            9.4        >100.0                                               80            9.5        >100.0                                               81            10.0       >100.0                                               82             0.35      100.0                                                83             0.55      >50.0                                                84            0.5        >50.0                                                85            0.8        60.0                                                 86            0.4        >100.0                                               87             0.25      >100.0                                               88            0.7        75.0                                                 89            0.5        38.0                                                 90             0.15      >100.0                                               91             0.15      >100.0                                               92             0.29      >100.0                                               93             0.35      >100.0                                               94             0.19      >100.0                                               95            0.5        >100.0                                               98             0.15      >100.0                                               99             0.15      >100.0                                               100            0.25      >100.0                                               101           1.5        >100.0                                               102           0.7        >100.0                                               103           5.0        >100.0                                               104           7.0        >100.0                                               105           3.0        >100.0                                               106           5.0        >100.0                                               107           2.5        >100.0                                               108           3.5        >100.0                                               109           2.0        >100.0                                               110           2.3        >100.0                                               ______________________________________                                    

Accordingly it has been definitely shown by the test results that allmodified oligodeoxyribonucleotides listed in Table 2 have a particularlyintensive anti-(HIV-1) activity at the concentration of less than 10μg/ml.

Unless otherwise specified, the base sequence (for example TGGGAGG) usedin the following chemical structures signifies the triethylamine salt ofthe appropriate oligodeoxyribonucleotide, not having a hydroxy group atboth the 5'- and 3'-positions.

The invention is further illustrated by the following Examples. In theExamples, all mesh sizes employ the Tyler standard, and nuclear magneticresonance spectra were obtained using trimethylsilane as an internalstandard, where indicated by the abbreviation "TMS". The amount ofoligodeoxyribonucleotide derivative prepared in each of these Exampleswas measured by means of the optical density at 260 nm OD (260 =m)!.

EXAMPLE 1

1(a) 5'-O-Tritylthymidine 2-cyanoethyl N,N-diisopropylphosphoramidite##STR19##

969 mg (2 mmol) of 5'-O-tritylthymidine J. Am. Chem. Soc., 80, 6212(1958)! were dried three times by azeotronic distillation with pyridine,after which it was dissolved in 10 ml of tetrahydrofuran. 1.39 ml (8mmol) of N,N-diisopropyl-N-ethylamine and 0.822 ml (4 mmol) of2-cyanoethyl N,N-diisopropylchlorophosphoramidite were then added to thesolution, and the resulting mixture was stirred at room temperature for30 minutes in an atmosphere of argon. At the end of this time, theresulting precipitate was filtered off from the reaction mixture, andthe filtrate was freed from the solvent by distillation under reducedpressure. The resulting residue was dissolved in 100 ml of ethylacetate, and the solution was washed twice, each time with 50 ml of anice-cooled 10% w/v aqueous solution of sodium carbonate. The solutionwas then dried over anhydrous sodium sulfate, after which the solventwas removed by distillation under reduced pressure. The resultingresidue was purified by column chromatography through 40 g of silica gel(70-230 mesh) using a 45:45:10 by volume mixture of methylene chloride,ethyl acetate and triethylamine as the eluent, to give 1.35 g (yield98%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.62, 7.57 (together 1H, two singlets); 7.46-7.20 (15H, multiplet);6.46-6.37 (1H, multiplet); 4.68 (1H, broad singlet); 4.19, 4.15(together 1H, two broad singlets); 3.90-3.30 (6H, multiplet); 2.63-2.28(4H, multiplet); 1.47 (3H, singlet); 1.23-1.00 (12H, multiplet).

1(b) A compound of formula 1(b): ##STR20##

Synthesis was effected using a Cyclone Plus (trade mark) DNA/RNAsynthesizer manufactured by MilliGen/Biosearch (a division of MillicoreLtd., Japan). Into this were charged the chemical reagents correspondingto the nucleotide residues in the above formula 1(b), to synthesise theabove oligonucleotide. A program cartridge for the amidite method wasinserted into the machine. The synthesis was carried out on a 15 μmolescale. In this case a 35 mM acetonitrile solution of5'-O-tritylthymidine 2-cyanoethyl N,N-diisopropylphosphoramiditeprepared as described in step (a) above! was used instead of a2-cyanoethyl phosphoramidite solution corresponding to thymidine. Thereaction column was a column for a 15.0 umol scale reaction, packed with5 μmol of G-CPG i.e. guanine-deoxyribonucleoside (G) coupled tocontrolled pore glass (CPG)!. The concentration of nucleotide on theglass filler was 35-44 μmol/g, and the CPG filler had an average poresize of 50 nm. The desired base sequence TGGGAG was input (as isconventional, the base sequence quoted here, as well as those referredto hereafter, include the base which has been coupled to the CPG), andthe program was run without acid-treatment after bond-formation with theterminal T, to give a derivative wherein the desired protectedoligonucleotide was coupled to the controlled pore glass (CPG). This wasdried in vacuo, removed from the column and immersed in about 10 ml of29% aqueous ammonia. It was then allowed to react at room temperaturefor about 2 days in a sealed vessel. At the end of this time, the CPGwas removed by filtration and washed twice, each time with 10 ml ofwater; the filtrate and the washings were then combined. The combinedmixture was then washed three times, each time with 30 ml of diethylether, after which the ammonia and diethyl ether was removed byevaporation in vacuo. The resulting aqueous solution was concentrated toabout 3 ml by evaporation under reduced pressure, and the concentratedsolution was filtered with the aid of a millipore filter (0.45 μm). Thefiltrate was divided auto 3 portions and each portion was purified byreverse phase high performance liquid chromatography through a 20.0×250mm column, Inertsil PREP-ODS (trade mark), which had previously beenequilibrated with a 0.1M aqueous triethylammonium acetate buffer (TEAA)(pH 7.3), containing 20% by volume of acetonitrile, and monitored byultraviolet light at 254 nm. The desired product was eluted using agradient elution method with 0.1M TEAA containing acetonitrile atconcentrations ranging from 20 to 50% by volume, with a linear gradientof 8 ml/minute over a period of 30 minutes. Fractions eluted after 17.2minutes were collected and the solution was freed from acetonitrile byevaporation under reduced pressure, after which the resulting aqueoussolution was lyophilized. The product thus obtained was dissolved in 50ml of water and again lyophilized, to produce 94.8 OD (260 nm) of thecompound of formula 1(b) as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 23.3 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, PH 7.3; eluent B: acetonitrile; 20-50% B by volume,30 minutes, linear gradient; 1 ml/minute; 254 nm).

EXAMPLE 2

(2a) 5'-Tritylamino-5'-deoxythymidine

557 mg of trityl chloride were added to a solution of 560 mg (2 mmol) of3'-O-acetyl-5'-amino-5'-deoxythymidine which had been prepared by theprocedure reported by J. P. Horwitz et al. in J. Org. Chem., 27, 3045(1962)! in 20 ml of dry pyridine, and the resulting mixture was heatedunder reflux or 1 hour whilst excluding moisture. After thedisappearance of the starting compound had been ascertained by thinlayer chromatography (using methylene chloride containing 5% by volumemethanol as the developing solvent), the solvent was removed from thereaction mixture by distillation under reduced pressure. The resultingresidue was mixed with 10 ml each of methanol and water, and then themixture was concentrated by distillation under reduced pressure. Thisoperation was repeated three times, after which the residue wasdissolved in 30 ml of ethyl acetate, and the resulting solution waswashed with 20 ml each of a saturated aqueous solution of sodiumchloride, 0.2N aqueous hydrochloric acid and a 5% aqueous solution ofsodium hydrogencarbonate. The organic solution was then dried overanhydrous magnesium sulfate, and the solution was then evaporated todryness under reduced pressure. The residue was dissolved in 30 ml ofmethanol saturated with ammonia gas and the flask holding the solutionwas tightly closed. It was then allowed to stand overnight at roomtemperature. At the end of this time, the reaction mixture was freedfrom the solvent by distillation under reduced pressure, and the residuewas dissolved in 10 ml of methylene chloride. The solution was purifiedby column chromatography through silica gel, using methylene chloridecontaining 5% by volume of methanol as the eluent. Fractions containingthe desired compound were combined and evaporated to dryness underreduced pressure. By lyophilizing the residue from benzene, 338 mg ofthe title compound were obtained as a white powder.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.38 (1:H, broad singlet); 7.48-7.18 (15H, multiplet); 7.04 (1H,multiplet); 6.67 (1H, triplet, J=6.60 Hz); 4.35-4.29 (1H, multiplet);4.01-3.95 (1H, multiplet); 2.62-2.06 (5H, multiplet); 1.84 (3H,singlet).

2(b) 5'-Tritylamino-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite

0.15 g (0.31 mmol) of 5'-tritylamino-5'-deoxy-thymidine prepared asdescribed in step (a) above! was dried by azeotropic distillation withpyridine and then dissolved in 2 ml of methylene chloride. 0.23 ml (1.2mmol) of N,N-diisopropyl-N-ethylamine was then added to the resultingsolution, after which 0.08 ml (0.36 mmol) of 2-cyanoethylN,N-diisopropylchlorophosphoramidite was added over a period of 2minutes in a stream of nitrogen. The resulting mixture was then stirredat room temperature for 60 minutes. At the end of this time, it wasconfirmed that the starting compound had disappeared by thin layerchromatography, and the reaction mixture was diluted with 30 ml of ethylacetate. The resulting organic solution was washed with a saturatedaqueous solution of sodium hydrogencarbonate and with a saturatedaqueous solution of sodium chloride, in that order. The organic layerwas through a 1PS (trade mark) filter paper (Whatman), and the filtratewas freed from the solvent by distillation under reduced pressure. Theresulting residue was purified by column chromatography through 15 g ofsilica gel (70-230 mesh), using ethyl acetate as the eluent, to give0.19 g (yield 89%) of the title compound as a foamy substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.50-7.19 (15H, multiplet); 7.15, 7.06 (together 1H, two singlets);6.30-6.26 (1H, multiplet); 4.55-4.35 (1H, multiplet); 4.12-4.07 (1H,multiplet); 3.84-3.53 (4H, multiplet); 2.64-2.09 (6H, multiplet); 1.86,1.84 (together 3H, two singlets); 1.19-1.10 (12H, multiplet).

2(c) A compound of formula 2(c): ##STR21##

Following a procedure similar to that described in Example 1(b), butusing 5'-tritylamino-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Preparation2(b)! in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (preparative C18, Waters, 1.5×15 cm; 50 mM aqueoustrimethylammonium hydrogencarbonate buffer (TEAB), pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). The eluate was worked up in asimilar manner to that described in Example 1b to give 168 OD (260 nm)of the title compound as an amorphous solid. Analysis by reverse phasehigh performance liquid chromatography (Inertsil ODS, 6×150 mM; eluentA: 0.1M TEAA, pH 7.5; eluent 3: acetonitrile; ;0-60% B by volume, 20minute; linear gradient; 1 ml/minute; 260 mm) showed that the sample hada retention lime of 19.20 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 3

3(a) 5'-O-Benzhydrylthymidine

350 mg (8 mmol) of sodium hydride (as a 55% w/w dispersion in mineraloil) were added to a solution of 1.426 g (4 mmol) of 3'-O-(1,1-dimethylethyl)dimethylsilyl!thymidine Can. J. Chem., 56, 2768(1978)! in 8 ml of tetrahydrofuran under an atmosphere of argon, and theresulting mixture was stirred at 60° C. for 2 hours and then allowed tocool to room temperature. A solution of 988 mg (4 mmol) of benzylbromide in 2 ml of tetrahydrofuran was then added dropwise to themixture, followed by 300 mg (2 mmol) of sodium iodide. The reactionmixture was then stirred at room temperature for 17 hours, after whichit was freed from the solvent by distillation under reduced pressure.The concentrate was dissolved in 50 ml of ethyl acetate, and theresulting solution was washed twice each time with 50 ml of a saturatedaqueous solution of sodium chloride. It was then dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The residue was dissolved in 4 ml of tetrahydrofuran, and 4 mlof a 1M tetrahydrofuran solution of tetrabutylammonium fluoride wereadded to the solution. The resulting mixture was then stirred at roomtemperature for 2 hours. At the end of this time, the solvent wasremoved by distillation under reduced pressure, and the residue wasdissolved in 50 ml of ethyl acetate. The resulting solution was washedtwice, each time with 50 ml of a saturated aqueous solution of sodiumchloride. The mixture was dried over anhydrous magnesium sulfate, andthen the solvent was removed by distillation under reduced pressure. Theresidue was purified by column chromatography through 60 g of silica gel(230-400 mesh) using a gradient elution method, with methylene chloridecontaining from 1 to 2.5% by volume methanol as the eluent, to give377.7 mg (yield 23%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:9.85 (1H, broad singlet); 7.56 (1H, singlet); 7.38-7.20 (10H,multiplet); 6.45 (1H, triplet, J=6.92 Hz); 5.40 (1H, singlet); 4.62-4.58(1H, multiplet); 4.17-4.15 (1H, multiplet); 3.75-3.58 (2H, multiplet);2.47-2.22 (2H, multiplet); 1.36 (3H, singlet).

3(b) 5'-O-Benzhydrylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite ##STR22##

204.2 mg (0.5 mmol) of 5'-O-benzhydrylthymidine prepared as described instep (a) above! were dried three times by azeotropic distillation withpyridine and then dissolved in 2.5 ml of tetrahydrofuran. 0.348 ml (2mmol) of N,N-diisopropyl-N-ethylamine and 0.223 ml (1 mmol) of2-cyanoethyl N,N-diisopropylchlorophosphoramidite were added to thesolution under an atmosphere of argon, and the resulting mixture wasstirred at room temperature for 30 minutes. At the end of this time, thereaction mixture was freed from precipitates by filtration, and thefiltrate was concentrated by evaporation under reduced pressure. Theconcentrate was dissolved in 50 ml of ethyl acetate, and the resultingsolution was washed twice, each time with 50 ml of an ice-cooled 10% w/vaqueous solution of sodium carbonate and dried over anhydrous sodiumsulfate. The solvent was then removed by distillation under reducedpressure. The residue was purified by column chromatography through 30 gof silica gel (70-230 mesh), using a 45:45:10 by volume mixture ofmethylene chloride, ethyl acetate and triethylamine as the eluent.Fractions containing the title compound were combined and the solventwas distilled off. The same chromatography procedure was repeated, toobtain 213.4 mg (yield 70%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.55, 7.51 (together 1H, two singlets); 7.43-7.22 (10H, multiplet);6.48-6.42 (1H, multiplet); 5.44, 5.42 (together 1H, two singlets);4.73-4.64 (1H, multiplet); 4.25, 4.19 (together 1H, two broad singlets);3.90-3.55 (6H, multiplet); 2.68-2.24 (4H, multiplet); 1.39 (3H,singlet); 1.30-1.10 (12H, multiplet).

3(c) A compound of formula 3(c): ##STR23##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-benzhydrylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was divided into three portions and each portion waspurified by chromatography through a reverse phase high performanceliquid chromatography column (Inertsil PREP-ODS, 20.0×250 nm; eluent A:0.1M TEAA, pH 7.3; eluent B: acetonitrile; 15-45% B by volume, 30minutes, linear gradient; 7 ml/minute; 254 nm). Fractions eluted after20.2 minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b) to produce 76 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 17.3 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 10-40% B by volume,30 minutes, linear gradient; 2 ml/minute; 254 nm).

EXAMPLE 4

A compound of formula 4(a): ##STR24##

Following a procedure similar to that described in Example 1(b), butinputting the base sequence TGGGAGG to the DNA/RNA synthesizer describedin Example 1(b), the title compound was prepared. The reaction productwas purified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). Working up similar to thatdescribed in Example 1(b) gave 180 OD (260 nm) of the title compound asan amorphous solid. Analysis by reverse phase high performance liquidchromatography (Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAA, pH 7.5;eluent B: acetonitrile; 10-60% B by volume, 20 minutes; linear gradient;1 ml/minute; 260 nm) showed that the sample had a retention time of18.22 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 5

5(a) 5'-O- (1,1-Dimethylethyl)diphenylsilyl!thymidine

1.43 ml (5.5 mmol) of t-butyldiphenylsilyl chloride were added to asolution of 1.21 g (5 mmol) of thymidine and 0.749 g (11 mmol) ofimidazole in 10 ml of dimethylformamide under an atmosphere of argon,and the resulting mixture was stirred at room temperature for 140minutes. At the end of this time, the solvent was removed bydistillation under reduced pressure, and the resulting residue wasdissolved in 100 ml of methylene chloride. The solution was then washed5 times, each time with 100 ml of water. The solution was then driedover anhydrous magnesium sulfate, after which the solvent was distilledoff under reduced pressure. The residue was purified by columnchromatography through 100 g of silica gel (70-230 mesh) using agradient elution method, with methylene chloride containing from 0.5 to3% by volume of methanol as the eluent, to give 1.5 g (yield 62%) of thetitle compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:10.52 (1H, broad singlet); 7.73-7.32 (10H, multiplet); 7.57 (1H,singlet); 6.53-6.47 (1H, multiplet); 4.63 (1H, broad singlet); 4.48 (1H,broad singlet); 4.11 (1H, broad singlet); 4.04-3.85 (2H, multiplet);2.58-2.16 (2H, multiplet); 1.59 (3H, singlet); 1.10 (9H, singlet).

5(b) 5'-O- (1,1-Dimethylethyl)diphenylsilyl!thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 3(b), butusing 240 mg (0.5 mmol) of 5'-O-(1,1-dimethylethyl)diphenylsilyl!thymidine prepared as described in step(a) above!, 254.4 mg (yield 74.7%) of the title compound were obtained.

¹ H Nuclear Magnetic Resonance spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.69-7.36 (11H, multiplet); 6.43-6.38 (1H, multiplet); 4.70-4.62 (1H,multiplet); 4.16-4.09 (1H, multiplet); 4.04-3.55 (6H, multiplet);2.67-2.15 (4H, multiplet); 1.61 (3H, singlet); 1.22-1.05 (12H,multiplet).

5(c) A compound of formula 5(c): ##STR25##

Following a procedure similar to that described in Example 1(b), butusing 5'-O- (1,1-dimethylethyl)diphenylsilyl!thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was divided into three portions and each portion waspurified by chromatography through a reverse phase high performanceliquid chromatography column (Inertsil PREP-ODS, 20.0×250 mm; eluent A:0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume, 30minutes; linear gradient; 7 ml/minute; 254 m). Fractions eluted after22.4 minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b), to give 54 OD (260 nm) of the title compoundas an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 22.0 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume,30 minutes, linear gradient; 1 ml/minute; 254 nm).

EXAMPLE 6

6(a) 5'-O-(3,5-Dibenzyloxybenzyl)thymidine

175 mg (4 mmol) of sodium hydride (as a 55% w/w dispersion in mineraloil) were added to a solution of 713 mg (2 mmol) of 3'-O-(1,1-dimethylethyl)dimethylsilyl!thymidine Can. J. Chem., 56, 2768(1978)! in 4 ml of tetrahydrofuran under an atmosphere of argon, and theresulting mixture was stirred at 60° C. for 2 hours. At the end of thistime, the mixture was allowed to cool to room temperature, and then asolution of 767 mg (2 mmol) of 3,5-dibenzyloxybenzyl bromide Chem. Ber.,102, 2887 (1969)! in 1 ml of tetrahydrofuran was added dropwise. 149.9mg (1 mmol) of sodium iodide were then added to the resulting mixture,after which the mixture was stirred at room temperature for 16 hours. Atthe end of this time, the solvent was removed by distillation underreduced pressure, the residue was dissolved in 50 ml of ethyl acetateand the resulting solution was washed twice, each time with 50 ml of0.01N aqueous hydrochloric acid. The solution was then dried overanhydrous magnesium sulfate, after which the solvent was distilled offunder reduced pressure. The residue was purified by columnchromatography through 100 g of silica gel (230-400 mesh), using agradient elution method, with methylene chloride containing from 0.5 to3% by volume of methanol as the eluent, to give 637.3 mg of a mixturecontaining 3'-O-(1,-dimethylethyl)dimethylsilyl!-5'-O-(3,5-dibenzyloxybenzyl)thymidine.

The whole of this was dissolved in 1.93 ml of tetrahydrofuran. 1.93 mlof a 1M tetrahydrofuran solution of tetrabutylammonium fluoride wereadded to the solution, and the resulting mixture was stirred at roomtemperature for 30 minutes. At the end of this time, the solvent wasremoved by distillation under reduced pressure, and the resultingresidue was dissolved in 50 ml of ethyl acetate. This solution waswashed twice, each time with 50 ml of a saturated aqueous solution ofsodium chloride. The solution was then dried over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure and theresidue was purified by chromatography through 30 g of silica gel(230-400 mesh), using a gradient elution method, with methylene chloridecontaining from 1 to 3% by volume of methanol as the eluent, to give258.5 mg (yield 23.7%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.87 (1H, singlet); 7.52 (1H, singlet); 7.43-6.52 (13H, multiplet); 6.37(1H, triplet, J=6.75 Hz); 5.03 (4H, singlet); 4.51 (2H, doublet, J=3.30Hz); 4.50-4.44 (1X, multiplet); 4.06-4.03 (1H, multiplet); 3.77-3.63(2H, multiplet); 2.32-2.12 (2H, multiplet); 1.67 (3H, singlet).

6(b) 5'-O-(3,5-Dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 3(b), butusing 258.5 mg (0.475 mmol) of 5'-O-(3,5-dibenzyloxybenzyl)thymidineprepared as described in step (a) above!, 307.7 mg (87%) of the titlecompound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.56, 7.53 (together 1H, two singlets); 7.42-6.56 (13H, multiplet); 6.40(1H, triplet, J=6.60 Hz); 5.02 (4H, singlet); 4.67-4.58 (1H, multiplet);4.53, 4.51 (together 2H, two singlets); 4.23, 4.17 (together 1H, twobroad singlets); 3.90-3.52 (6H, multiplet); 2.68-2.53 (2H, multiplet);2.49-2.12 (2H, multiplet); 1.65 (3H, singlet); 1.18 (12H, doublet,J=5.94 Hz).

6(c) A compound of formula 6(c): ##STR26##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(3,5-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was obtained. Thereaction product was divided into three portions, and each portion waspurified by chromatography through a reverse phase high performanceliquid chromatography column (Inertsil PREP-ODS, 20.0×250 mm; eluent A:0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume, 30minutes; linear gradient; 7 ml/minute; 254 nm). Fractions eluted after19.8 minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b), to give 64.6 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 22.8 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% by volume,30 minutes. linear gradient; 1 ml/minute; 254 nm).

EXAMPLE 7

7(a) 5'-O-(3,4-Dibenzyloxybenzyl)thymidine

713 mg (2 mmol) of 3'-O- (1,1-dimethylethyl)dimethylsilyl!thymidine Can.J. Chem., 56, 2768 (1978)! were dissolved in 5 ml of tetrahydrofuran,and 175 mg (4 mmol) of sodium hydride (as a 55% w/w dispersion inmineral oil) were added to the resulting solution under an argonatmosphere. The mixture was then stirred at 60° C. for 2 hours. At theend of this time, the temperature of the mixture was reduced to roomtemperature, and then 678 mg (2 mmol) of 3,4-dibenzyloxybenzyl chloridewas added, followed by 149.9 mg (1 mmol) of sodium iodide, and theresulting mixture was stirred at room temperature for 19 hours, and thenat 60° C. for 5 hours. At the end of this time, the solvent wasdistilled off under reduced pressure, and the residue was dissolved in50 ml of ethyl acetate. The resulting solution was washed twice, eachtime with 50 ml of 0.01N aqueous hydrochloric acid; it was then driedover anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure. The residue was dissolved in 4 mlof tetrahydrofuran, and 4 ml of a 1M solution of tetrabutylammoniumfluoride in tetrahydrofuran was added to the solution. The mixture wasthen stirred at room temperature for 2 hours. At the end of this time,the solvent was removed by distillation under reduced pressure, and theresidue was dissolved in 50 ml of ethyl acetate. The resulting solutionwas washed twice, each time with 50 ml of a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Thesolvent was then removed by distillation under reduced pressure, and theresidue was applied to a chromatography column LiChroprep (trade mark)Si60, 40-63 μm, Groβe C, Merck! and eluted using a gradient elutionmethod, with methylene chloride containing from 1 to 4% by volume ofmethanol, to give 345.4 mg (yield 31.7%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.26 (1H, singlet); 7.50 (1H, singlet); 7.47-7.28 (10H, multiplet);6.91-6.79 (3H, multiplet); 6.36 (1H, triplet, J=6.75 Hz); 5.17 (4H,singlet); 4.47, 4.45 (together 2H, two singlets); 4.41-4.36 (1.H,multiplet); 4.04-4.01 (1H, multiplet); 3.72-3.56 (2H, multiplet);2.31-2.05 (2H, multiplet); 1.62 (3H, singlet).

7(b) 5'-O-(3,4-Dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

271.7 mg (0.499 mmol) of 5'-O-(3,4-dibenzyloxybenzyl)thymidine preparedas described in step (a) above! were dried three times by azeotropicdistillation with pyridine, after which it was dissolved in 2.5 ml oftetrahydrofuran. 0.348 ml (2 mmol) of N,N-diisopropyl-N-ethylamine and0.223 ml (1 mmol) of 2-cyanoethyl N,N-diisopropylchlorophosphoramiditewere added to the resulting solution, and the mixture was stirred atroom temperature under an argon atmosphere for 2 hours. At the end ofthis time, the solvent was removed by distillation under reducedpressure. The residue was dissolved in 50 ml of ethyl acetate, and theresulting solution was washed twice, each time with 50 ml of anice-cooled 10% w/v aqueous solution of sodium carbonate, and then driedover anhydrous sodium sulfate. The solvent was removed by distillationunder reduced pressure, and the resulting residue was applied to acolumn containing 30 g (70-230 mesh) of silica gel. It was then elutedwith a 45:45:10 by volume mixture of methylene chloride, ethyl acetateand triethylamine. The fractions containing the desired product werecombined, the solvent was removed by distillation under reducedpressure, and the resulting residue was applied to a column containing30 g (70-230 mesh) of silica gel. It was then eluted with a 6:3:1 byvolume mixture of methylene chloride, ethyl acetate and triethylamine,to give 286.9 mg (yield 77%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.07 (1H, broad singlet); 7.53, 7.51 (together 1H, two singlets);7.45-7.25 (10H, multiplet); 6.92-6.81 (3H, multiplet); 6.37 (1H,triplet, J=6.60 Hz); 5.15 (4H, singlet); 4.62-4.53 (1H, multiplet); 4.47(2H, singlet); 4.22, 4.14 (together 1H, two broad singlets); 3.90-3.53(6H, multiplet); 2.68-2.53 (2H, multiplet); 2.47-2.05 (2H, multiplet);1.58 (3H, singlet); 1.17 (12H, doublet, J=5.94 Hz).

7(c) A compound of formula 7(c): ##STR27##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was then divided into three portions and each portionwas purified by chromatography through a reverse phase high performanceliquid chromatography column (Inertsil PREP-ODS, 20.0×250 nm; eluent A:0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume, 30minutes; linear gradient; 7 ml/minute; 254 nm). Fractions eluted after22.5 minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b), to give 55.7 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 13.6 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume,30 minutes, linear gradient; 2 ml/minute; 254 nm).

EXAMPLE 8

A compound of formula 8(a): ##STR28##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)above! in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, using a column packed with 5 μmol ofA-CPG i.e. adeninedeoxyribonucleoside (A) coupled to controlled poreglass! and inputting a base sequence TGGGA to the synthesizer, the titlecompound was prepared. The reaction product was divided into threeportions and each portion was purified by chromatography through areverse phase high performance liquid chromatography column (InertsilPREP-ODS, 20.0×250 nm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 7ml/minute; 254 nm). Fractions eluted after 23.3 minutes were combinedand worked up in a similar manner to that described in Example 1(b), togive 86.2 OD (260 nm) of the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 256.

Retention time: 14.2 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50 B by volume,30 minutes, linear gradient; 2 ml/minute; 254 nm).

EXAMPLE 9

A compound of formula 9(a): ##STR29##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)above! in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, and inputting a base sequence TGGG tothe synthesizer, the title compound was prepared. The reaction productwas divided into three portions and each portion was purified bychromatography through a reverse phase high performance liquidchromatography column (Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1MTEAA, pH 7.3; eluent B: acetonitrile; 25-55% B by volume, 30 minutes;linear gradient; 7 ml/minute; 254 nm). Fractions eluted after 19.5minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b), to give 77.5 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) mm: 255.

Retention time: 14.8 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume,30 minutes, linear gradient; 2 ml/minute; 254 nm).

EXAMPLE 10

A compound of formula 10(a): ##STR30##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)above! in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, and inputting a base sequence TGGGG tothe synthesizer, the title compound was prepared. The reaction productwas divided into three portions and each portion was purified bychromatography through a reverse phase high performance liquidchromatography column (Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1MTEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume, 30 minutes;linear gradient; 7 ml/minute; 254 nm). Fractions eluted after 22.9minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b), to give 19.8 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 14.1 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume,30 minutes, linear gradient; 2 ml/minute; 254 nm).

EXAMPLE 11

11(a) 5'-O- (Pyren-1-yl)methyl!thymidine

A mixture of 875 mg of sodium hydride (as a 55% w/w dispersion inmineral oil) in 5 ml of dimethyl sulfoxide was stirred at roomtemperature for 30 minutes in an atmosphere of nitrogen, and then asolution of 2.42 g (10 mmol) of thymidine in 5 ml of dimethyl sulfoxidewas added dropwise to the resulting mixture. The mixture was stirred atroom temperature for 30 minutes, after which a suspension of 2.51 g (10mmol) of 1-(chloromethyl)pyrene Acta Chem. Scand., 10, 1362 (1936)! in15 ml of dimethyl sulfoxide was added. The mixture was then stirred atroom temperature for 90 minutes. At the end of this time, the reactionmixture was poured into 100 ml of ice-water, and the aqueous mixture wasextracted with 100 ml of ethyl acetate and then with 100 ml of methylenechloride. The extract was dried over anhydrous magnesium sulfate, andthen the solvent was removed by distillation under reduced pressure. Theresidue was purified by column chromatography through 150 g of silicagel (230-400 mesh), using a gradient elution method, with mixtures ofmethylene chloride containing from 0 to 4% by volume of methanol as theeluent, to give 292.4 mg (yield 6.4%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethylsulfoxide, 270 MHz, TMS), δ ppm: 8.44-8.07 (9H, multiplet); 7.44 (1H,singlet); 6.19 (1H, triplet, J=6.75 Hz); 5.33 (1H, doublet, J=5.4 Hz);5.29 (2H, singlet); 4.37-4.30 (1H, multiplet); 4.00-3.96 (1H,multiplet); 3.92-3.79 (2H, multiplet); 2.10-2.04 (2H, multiplet); 1.20(3H, singlet).

11(b) 5'-O- (Pyren-1-yl)methyl!thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

91.3 mg (0.2 mmol) of 5'-O- (pyren-1-yl)methyl!thymidine prepared asdescribed in step (a) above! were dried three times by azeotropicdistillation with pyridine, after which it was suspended in 2 ml oftetrahydrofuran. 139 μl (0.8 mmol) of N,N-diisopropyl-N-ethylamine and89 μl (0.4 mmol) of 2-cyanoethyl N,N-diisopropylchlorophosphoramiditewere added to the suspension under an atmosphere of argon, and theresulting mixture was stirred at room temperature for 30 minutes. At theend of this time, the precipitates were removed by filtration, and thefiltrate was freed from the solvent by distillation under reducedpressure. The residue was dissolved in 20 ml of ethyl acetate, and theresulting solution was washed twice, each time with 20 ml of anice-cooled 10% w/v aqueous solution of sodium carbonate. The solutionwas dried over anhydrous sodium sulfate, and then the solvent wasremoved by distillation under reduced pressure. The resulting residuewas purified by column chromatography through 30 g of silica gel (70-230mesh), using a 6:3:1 by volume mixture of methylene chloride, ethylacetate and triethylamine as the eluent, to give 100.2 mg (yield 76%) ofthe title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.36-7.99 (9H, multiplet); 7.50, 7.46 (together 1H, two singlets); 6.35(1H, triplet, J=6.60 Hz); 5.38-5.22 (2H, multiplet); 4.60-4.50 (1H,multiplet); 4.25-4.17 (1H, multiplet); 4.01-3.77 (2H, multiplet);3.73-3.44 (4H, multiplet); 2.78-2.09 (4H, multiplet); 1.31, 1.29(together 3H, two singlets); 1.10-1.05 (12H, multiplet).

11(c) A compound of formula 11(c): ##STR31##

Following a procedure similar to that described in Example 1(b), butusing 5'-O- (pyren-1-yl)methyl!-thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!in place of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was divided into three portions and each portion waspurified by chromatography through a reverse phase high performanceliquid chromatography column (Inertsil PREP-ODS, 20.0×250 mm; eluent A:0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume, 30minutes; linear gradient; 7 ml/minute; 254 nm). Fractions eluted after15.4 minutes were combined and worked up in a similar manner to thatdescribed in Example 1(b), to give 80 OD (260 nm) or the title compoundas an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 243.

Retention time: 16.4 minutes

High performance liquid chromatography (YMC-Pack A-312, S-5, 120A, ODS;eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 20-50% B by volume,30 minutes, linear gradient; 1 ml/minute; 254 nm).

EXAMPLE 12

12(a) O-Dimethoxytrityl ethylene glycol

3.1 g (50 mmol) of ethylene glycol were dried by azeotropic distillationwith pyridine and then dissolved in 40 ml of pyridine. 3.38 g (10 mmol)of 4,4'-dimethoxytrityl chloride were added to the solution, and theresulting mixture was stirred at room temperature for 2 hours. Afterdisappearance of the starting compound had been confirmed by thin layerchromatography, 5 ml of methanol were added to the reaction mixture, andthe mixture was then concentrated to about one half of its volume bydistillation under reduced pressure. The concentrate was dissolved in100 ml of methylene chloride, and the resulting solution was washed witha saturated aqueous solution of sodium hydrogencarbonate. The organicsolution was filtered through a 1PS filter paper (Whatman), and thefiltrate was freed from the solvent by distillation under reducedpressure. The residue was purified by column chromatography through 100g of silica gel (70-230 mesh) using methylene chloride containing 1% byvolume of methanol as the eluent, to give 1.97 g of the title compoundas a gummy substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.45-6.82 (13H, multiplet); 3.79 (6H, singlet); 3.75 (2H, triplet,J=4.95 Hz); 3.25 (2H, triplet, J=4.62 Hz); 1.95 (1H, triplet).

12(b) A compound of formula 12(b): ##STR32##

0.18 g (0.5 mmol) of O-dimethoxytrityl ethylene glycol prepared asdescribed in step (a) above! was dried by azeotropic distillation withpyridine and then dissolved in 2 ml of methylene chloride. 75 mg (0.75mmol) of succinic anhydride and 92 mg (0.75 mmol) of4-(dimethylamino)pyridine were then added to the solution, and theresulting mixture was stirred for 1 hour. After the disappearance of thestarting material had been confirmed by thin layer chromatography, thereaction mixture was diluted with methylene chloride, and the dilutedsolution was washed with a 0.5M aqueous solution of potassiumdihydrogenphosphate (pH 5.0) and with water in that order. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasremoved by distillation under reduced pressure, to giveO-dimethoxytrityl ethylene glycol monosuccinate.

The whole of this compound was dried by azeotropic distillation withpyridine and then dissolved in 3 ml or dimethylformamide. 0.16 g (0.75mmol) of pentachlorophenol and 0.16 g (0.75 mmol) of1,3-dicyclohexylcarbodiimide were then added to the solution, and theresulting mixture was stirred at room temperature for 42 hours. At theend of this time, insoluble materials were filtered off, and thefiltrate was concentrated by distillation under reduced pressure. Theresidue was mixed with benzene, and the resulting insoluble materialswere again filtered off, after which the solvent was removed bydistillation under reduced pressure.

0.25 g (0.2 mmol) of the residue produced as described above wasdissolved in 4 ml of dimethylformamide, and 60 μl (0.44 mmol) oftriethylamine and 2.0 g of (3-aminopropyl)-CPG (containing 0.129 mmol/gof amino groups) were added to the solution. The resulting mixture wasthen allowed to stand at room temperature for 36 hours. At the end ofthis time, the CPG carrier was collected by filtration, washed withmethylene chloride and then dried in vacuo. The CPG carrier was mixedwith 10 ml each of cap A and B solutions (Millipore Ltd., Japan) and themixture was allowed to stand for 10 minutes in order to acetylate anyamino group remaining to be reacted. The reaction product was thenwashed with pyridine and methylene chloride, in that order, after whichit was dried in vacuo, to give the title compound of formula 12(b). CapA solution is a 1:9 by volume mixture of acetic anhydride andtetrahydrofuran, and cap B solution is a 1:4 by volume mixture ofN-methylimidazole and tetrahydrofuran.

The proportion of residues derived from O-dimethoxytrityl ethyleneglycol introduced into the compound of Example 12(b) was quantitativelyanalyzed as follows. A mixture of 9.6 mg of the compound of Example12(b) and a deblock solution (a solution of dichloroacetic acid inmethylene chloride; Millipore Ltd., Japan) was shaken for 3 minutes andthen sufficient methylene chloride was added to the solution to make thetotal volume 20 ml. 0.4 ml of this solution was taken in a test-tube andused for measurement. The sample solution was freed from the solvent bydistillation under reduced pressure, and the residue was dissolved in a3:2 by volume mixture of perchloric acid and ethanol. The absorbance ofthe dimethoxytrityl cation in the solution was determined at 500 nm.

As a result, it was found that the amount of dimethoxytrityl groupintroduced was 40.0 μmol/g.

12(c) A compound of formula 12(c): ##STR33##

Following a procedure similar to that described in Example 16(b), butusing a column packed with 125 mg (5 μmol) of the compound of Example12(b) and inputting the base sequence TGGGAGZ (in which Z is a dummycode, as explained in Example 17) to the synthesizer, the title compoundwas prepared using a DNA/RNA synthesizer as described in Example 1(b).The reaction product was purified by chromatography through a reversephase silica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB,pH 7.5; 20-50% acetonitrile; linear gradient; 254 nm) and worked up in asimilar manner to that described in Example 1(b), to give 165 OD (260nm) of the title compound as an amorphous solid. Analysis by reversephase high performance liquid chromatography (Inertsil ODS, 6×150 mm;eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% B by volume,20 minutes; linear gradient; 1 ml/minute; 260 nm) showed that the samplehas a retention time of 18.76 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm. 254.

EXAMPLE 13

A compound of formula 13(a): ##STR34##

Following a procedure similar to that described in Example 12(c), butusing 151 mg (5 μmol) of 3'-amino-ON CPG (trade mark for a product ofClontech), the title compound was prepared. The product was purified bychromatography through a reverse phase silica gel column (PreparativeC18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50% acetonitrile; lineargradient; 254 nm) and worked up in a similar manner to that described inExample 1(b), to give 165 OD (260 nm) of the title compound as anamorphous solid. Analysis by reverse phase high performance liquidchromatography (Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAK, pH 7.5;eluent B: acetonitrile; 10-60% B by volume, 20 minutes; linear gradient;1 ml/minute; 260 nm) showed that the sample has a retention time of18.76 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 14

A compound of formula 14(a): ##STR35##

A procedure similar to that described in Example 12(c) was repeated, butwith the following modification. The compound of Example 12(b) was firstcoupled with guaninedeoxyribonucleotide-β-amidite at the terminal3'-position, and the column was then removed from the synthesizerwithout oxidation by an oxidizing solution. 5 ml of an acetonitrilesolution of tetraethylthiuram disulfide (TETD) (Applied Biosystems) werethen added to the column, which was then allowed to stand at roomtemperature for 15 minutes. The column was then washed with acetonitrileand installed to the synthesizer.

In the purification step, chromatography was carried out through areverse phase silica gel column (Preparative C18, Waters, 1.5×15 cm; 50mM TEAB, pH 7.5; 20-50% acetonitrile; linear gradient; 254 nm). Byworking up in a similar manner to that described in Example 1(b), 33 OD(260 nm) of the title compound was obtained as an amorphous solid.Analysis by reverse phase high performance liquid chromatography(Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10-60% B by volume, 20 minutes; linear gradient; 1ml/minute; 260 nm) showed that the sample had a retention time of 18.92minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 15

15(a) 5'-O-Trityl-N-benzoyl-2'-deoxycytidine

3.31 g (10 mmol) of N-benzoyl-2'-deoxycytidine were added to 25 ml ofpyridine, and then 3.07 g (11 mmol) of trityl chloride were added to thesuspension. The resulting suspension was stirred at 100° C. for 1 hour,after which it was allowed to cool to room temperature. The pyridine wasthen removed by distillation under reduced pressure. The resultingresidue was dissolved in a mixture of ethyl acetate and a saturatedaqueous solution of sodium chloride. The organic layer was separated andwashed twice, each time with a saturated aqueous solution of sodiumchloride. The solution was then dried over anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. The resulting residue was purified by column chromatographythrough silica gel (Lober column Si-60, Size C) using a gradient elutionmethod, with mixtures of methanol and methylene chloride ranging from2:98 to 5:95 by volume as the eluent, to give 1.47 g (yield 26%) of thetitle compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.72 (1X, broad singlet); 8.26 (1H, doublet, J=7.3 Hz); 7.89 (1H,doublet, J=7.3 Hz); 7.26-7.64 (20H, multiplet); 6.29 (1H, triplet, J=5.9Hz); 4.48-4.53 (1H, multiplet); 4.12-4.16 (1H, multiplet); 3.42-3.57(2H, multiplet); 2.23-2.77 (2H, multiplex); 2.51 (1H, broad singlet).

15(b) 5'-O-Trityl-N-benzoyl-2'-deoxycytidine 2-cyanoethylN,N-diisopropylphosphoramidite

402 mg (0.7 mmol) of 5'-O-trityl-N-benzoyl-2'-deoxycytidine prepared asdescribed in step (a) above! were dried by azeotropic distillation withpyridine and then dissolved in 3.5 ml of methylene chloride. 60 mg (0.35mmol) of diisopropylammonium tetrazolide were added to the solution. 245μl (0.77 mmol) of 2-cyanoethylN,N,N',N'-tetraisopropylphosphorodiamidite were then added dropwise,under an atmosphere of argon. The resulting mixture was stirred at roomtemperature for 3.5 hours under same atmosphere. At the end of thistime, the methylene chloride was removed by distillation under reducedpressure. The resulting residue was dissolved in ethyl acetate, and thesolution was washed with a 10% w/v aqueous solution of sodium carbonateand with a saturated aqueous solution of sodium chloride, in that order.The solution was then dried over anhydrous magnesium sulfate, afterwhich the solvent was removed by distillation under reduced pressure,and the residue was purified by column chromatography through 23 g ofsilica gel (70-230 mesh), using ethyl acetate as the eluent, to give 337mg (yield 62%) of the title compound as a foam substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.87 (1H, broad singlet); 8.52 & 8.43 (1H, doublet, J=7.3 Hz); 8.12 &8.11 (1H, doublet, J=7.3 Hz); 7.23-7.86 (20H, multiplet); 6.49-6.55 (1H,multiplet); 4.79-4.91 (1H, multiplet); 4.46-4.47 (1H, multiplet);3.60-4.10 (6H, multiples); 2.46-3.08 (4H, multiplet); 1.29-1.40 (12H,multiplet).

15(c) A compound of formula 15(c): ##STR36##

A procedure similar to that described in Example 1(b) was repeated,except that a 35 mM acetonitrile solution of the compound of Example15(b) was placed in the amidite bottle (referred to as "X") and the basesequence XGGGG was input to the synthesizer. The 90% aqueous formamidesolution containing the title compound thus obtained was heated at 95°C. for 5 minutes and then chilled in ice immediately. The reactionmixture was then divided into four portions and each was purified byreverse phase high performance liquid chromatography (Inertsil PREP-ODS20.0×250 mm; eluent A: 0.1M TEAA pH 7.0; eluent B: acetonitrile; 10 to60% B by volume, 30 minutes; linear gradient; 7 ml/minute; 260 nm;column temperature 60° C.). Fractions eluted after 20.9 minutes werecollected and worked up in a similar manner to that described in Example1(b), to give 68 OD (260 nm) of the title compound as an amorphoussolid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 13.25 minutes

by high performance liquid chromatography (Inertsil ODS-2: 6×150 mm;eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10 to 60% B byvolume, 20 minutes, linear gradient; 1 ml/minute; 260 nm)!.

EXAMPLE 16

16(a) A compound of formula 16(a): ##STR37##

0.26 g (0.5 mmol) of O-dimethoxytrityl hexaethylene glycol Nucleic AcidsRes., 18, 6353 (1990)! was dried by azeotropic distillation withpyridine and then dissolved in 2 ml of methylene chloride. 75 mg (0.75mmol) of succinic anhydride and 92 mg (0.75 mmol) of4-(dimethylamino)pyridine were then added to the solution, and theresulting mixture was stirred for 2 hours. After completion of thereaction had been confirmed by thin layer chromatography, the reactionmixture was diluted with methylene chloride, and the diluted mixture waswashed with a 0.5M aqueous solution of potassium dihydrogenphosphate (pH5.0) and with water, in that order. The organic layer was then driedover anhydrous sodium sulfate, and the solvent was removed bydistillation under reduced pressure, to give O-dimethoxytritylhexaethylene glycol monosuccinate.

The whole of this product was dried by azeotropic distillation withpyridine and then dissolved in 3 ml of dimethylformamide. 0.23 g (0.37mmol) of pentachlorophenol and 0.12 g (0.56 mmol) of1,3-dicyclohexylcarbodiimide were added to the solution, and theresulting mixture was stirred at room temperature for 16 hours. At theend of this time, the insoluble materials which had precipitated werefiltered off, and the filtrate was freed from the solvent by evaporationunder reduced pressure. The residue was dissolved in benzene, and theresulting insoluble materials were again filtered off, after which thesolvent was removed by distillation under reduced pressure.

30 μl (0.22 mmol) of triethylamine and 1.0 g of (3-aminopropyl)-CPG(containing 0.129 mmol/g of amino groups) were then added to a solutionof 0.23 g (0.18 mmol) of the residue in 5 ml of dimethylformamide, andthe resulting mixture was allowed to stand at room temperature for 24hours. At the end of this time, the CPG carrier was collected byfiltration and washed with methylene chloride, after which it was driedin vacuo. In order to acetylate the amino groups remaining unreacted,the CPG carrier was mixed with 3 ml each of cap A and B solutions(Millipore Ltd., Japan) and the mixture was allowed to stand for 10minutes. The reaction product was then washed with pyridine and withmethylene chloride, in that order, after which it was dried in vacuo toproduce the title compound.

The amount of O-dimethoxytrityl hexaethylene glycol residues introducedinto the compound of Example 16(a) was determined as follows. Thecompound (9.7 mg) of the Example 16(a) was accurately measured and adeblock solution (a methylene chloride solution of dichloroacetic acid;Millipore Ltd., Japan) was added thereto. The mixture was shaken for 3minutes, and then sufficient methylene chloride was added to make 20 ml.0.4 ml of this was taken up into a test tube and the solvent was removedby distillation under reduced pressure. 3 ml of a 3:2 by volume mixtureof perchloric acid and ethanol were added to the residue, and theabsorbance (ε=71,700) of the dimethoxytrityl cation at 500 nm wasmeasured.

The amount of dimethoxytrityl group introduced was 59.1 μmol/g.

16(b) A compound of formula 16(b): ##STR38##

Following a procedure similar to that described in Example 12(c), butusing a column packed with 85 mg (5 μmol) of the compound of Example16(a), the title compound was prepared. The product was purified bychromatography through a reverse phase silica gel column (PreparativeC18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 5-50% by volumeacetonitrile; linear gradient; 254 nm). By working up in a similarmanner to that described in Example 1(b), the title compound of formula16(b) was obtained having 151 OD (260 nm) as an amorphous solid.Analysis by reverse phase high performance liquid chromatography(Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10-60% B by volume, 20 minutes; linear gradient; 1ml/minute; 260 nm) showed that the sample had a retention time of 18.50minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 17 A Compound of Formula 17(a) ##STR39##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 85 mg (5 μmol) of the compound of Example16(a) and using a 35 mM acetonitrile solution of O-dimethoxytritylhexaethylene glycol a O-(2-cyanoethyl N,N-diisopropylphosphoramidite)Nucleic Acids Res., 18, 6353 (1990)! placed in the amidite bottle (andreferred to herein as "X") and by inputting the base sequence TGGGAGXZto the synthesizer, the title compound was prepared. In this Example andelsewhere, X is as defined above and Z represents a dummy code, that isa code entered on the synthesizer which does not input an actual base;when inputting the dummy code to the synthesizer, any of the codes A, G,C, T or X may be input, but will not result in a base being added to thesequence. The product was purified by chromatography through a reversephase silica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB,pH 7.5; 5-50% acetonitrile; linear gradient; 254 nm). By working up in amanner similar to that described in Example 1(b), the title compoundhaving 136 OD (260 nm) was obtained as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% byvolume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample had a retention time of 18.32 minutes.

Ultraviolet Absorption Spectrum (H₂ O) , λ_(max) nm: 254.

EXAMPLE 18 A Compound of Formula 18(a): ##STR40##

Following a procedure similar to that described in Example 17, butinputting the base sequence TGGGAGXXZ (in which X and Z are as definedin Example 17) to the synthesizer, the title compound was prepared. Theproduct was purified by chromatography through a reverse phase silicagel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5;5→50% acetonitrile; linear gradient; 254 nm). It was then worked up in amanner similar to that described in Example 1(b), to give 136 OD (260nm) of the title compound of formula 18(a) as an amorphous solid.Analysis by reverse phase high performance liquid chromatography(Inertsil ODS, 6×150 nm; eluent A: 0.1M TEAA. pH 7.5; eluent B:acetonitrile; 10→60% B by volume, 20 minutes; linear gradient; 1ml/minute; 260 nm) showed that the sample had a retention time of 18.20minutes.

Ultra-violet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 19 A Compound of Formula 19(a): ##STR41##

Following a procedure similar to that described in Example 17, butinputting the base sequence TGGGAGXXXZ (in which X and Z are as definedin Example 17) to the synthesizer, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 5-50% acetonitrile; linear gradient; 254 nm). It was then worked upin a manner similar to that described in Example 1(b), to give the titlecompound having 110 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 mm) showed thatthe sample had a retention time of 17.99 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 20 A Compound of Formula 20(a) ##STR42##

Following a procedure similar to that described in Example 2(c), butusing a column packed with 85 mg (5 μmol) of the compound of Example16(a) and inputting the base sequence TGGGAGZ (in which Z is as definedin Example 17) to the DNA/RNA synthesizer described in Example 1(b), thetitle compound was prepared. The product was purified by chromatographythrough a reverse phase silica gel column (Preparative C18, Waters,1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50% acetonitrile; linear gradient; 254nm). It was then worked up in a manner similar to that described inExample 1(b), to give the title compound having 177 OD (260 nm) as anamorphous solid. Analysis by reverse phase high performance liquidchromatography (Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAA, pH 7.5;eluent B: acetonitrile; 10-60% B by volume, 20 minutes; linear gradient;1 ml/minute; 260 nm) showed that the sample had a retention time of19.10 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 21 21(a) A Compound of Formula 21(a): ##STR43##

A solution of 250 mg of 5'-phosphate ON (a trade mark for a product ofClontech) in 5.2 ml of acetonitrile and a column packed with 15 μmol ofC-CPG Millipore Ltd., Japan) were used in the DNA/RNA synthesizerdescribed in Example 1(b), to prepare the title compound quantitatively.

21(b) A Compound of Formula 21(b): ##STR44##

5 ml of a deblock solution (Millipore Ltd., Japan) were added to afilter-equipped column packed with 115 mg (4 μmol) of the compound ofExample 21(a). It was then allowed to stand for one minute, after whichit was washed with 5 ml of methylene chloride, and then treated with adeblock solution for one minute. The mixture was then washed with 5 mlof methylene chloride and with 5 ml of pyridine, in that order, afterwhich it was azeotropically distilled with pyridine. A solution of 20 mgof triethylammonium 5'-O-dimethoxytrityl-2-N-isobutyryl-2'-deoxyguanosine-3'-O-(2-chlorophenyl)-phosphate (NucleicAcids Res., 8, 5461 (1980)1 in 0.5 ml of pyridine was then added to thedistillate, after which the solvent was removed by distillation underreduced pressure. A solution of 40 mg of2,4,6-trimethylbenzenesulfonyl-3-nitrotriazole in 0.5 ml of pyridine wasadded to the residue, and the resulting mixture was heated to 40° C. for30 minutes. The reaction mixture was then washed three times, each timewith 5 ml of pyridine, and then 2.5 ml of cap A solution (MilliporeLtd., Japan) and 2.5 ml of cap B solution (Millipore Ltd., Japan) wereadded to the mixture. The mixture was allowed to stand for 3 minutes,after which it was washed three times, each time with 5 ml of methylenechloride, to give the title compound.

21(c) A Compound of Formula 21(c) ##STR45##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 115 mg (4 μmol) of the compound of Example21(b) and thyminedeoxyribonucleotide-β-amidite (Millipore Ltd., Japan)instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 5-50% acetonitrile; linear gradient; 254 nm). It was then worked upin a manner similar to that described in Example 1(b), to give the titlecompound having 85 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-50% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample had a retention time of 21.5 minutes,

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 22 22(a) Triethylammonium5'-O-dimethoxytrityl-2-N-isobutyryl-2'-deoxyguanosine-3'-O-phenylphosphate

0.8 g (11.55 μmol) of 1,2,4-triazole was dried by azeotropicdistillation with pyridine and then suspended in 10 ml of dioxane. 0.52ml (3.5 mmol) of phenyl phosphorodichloridate was added to thesuspension, followed by 1.0 ml (7.35 mmol) of triethylamine, whilstice-cooling and stirring, and the temperature was then allowed to riseto room temperature. The mixture was stirred for 2 hours, after whichthe hydrochloride deposited was filtered off, to produce a dioxanesolution containing 0.35 mmol/ml of phenyl phosphoro-bis(triazolidate).

1 ml (0.35 mmol) of the dioxane solution of phenylphosphorobis(triazolidate) prepared as described above was added to 0.15g (0.23 mmol) of 5'-O-dimethoxytrityl-2-N-isobutyryl-2'-deoxyguanosineMethods Enzymol., 65, 610 (1980)), and the resulting mixture was stirredat room temperature for 3 hours. At the end of this time, about 10 ml of30% by volume aqueous pyridine were added. The reaction mixture was thenextracted with 30 ml of methylene chloride, and the extract was washedwith 0.1M TEAB. The solvent was removed by distillation under reducedpressure, and the resulting residue was dissolved in 1 ml of methylenechloride and triturated with 30 ml of a 1:1 by volume mixture of hexaneand diethyl ether, containing 1% by volume triethylamine, to give 81 mg(yield 40%) of the title compound as a powder.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:

12.07 (1H, broad singlet);

9,67 (1H, broad singlet);

7.80-7.64 (1H, multiplet);

7.47-6.91 (18H, multiplet);

6.12-6.10 (1H, multiplet);

5.48-5.45 (1H, multiplet);

4.64-4.58 (1H, multiplet);

4.28 (1H, multiplet);

3.74 (6H, singlet);

3.38-3.18 (2H, multiplet);

2.98-2.89 (6H, multiplet);

2.73-2.51 (2H, multiplet);

2.34-2.29 (1H, multiplet);

1.25-1.19 (9H, multiplet);

1.12-0.99 (6H, multiplet).

22(b) A Compound of Formula 22(b): ##STR46##

Following a procedure similar to that described in Example 21(b), butusing 143 mg (5 μmol) of the compound of Example 21(a) and the compoundof Example 22(a), the title compound was obtained.

22(c) A Compound of Formula 22(c): ##STR47##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (5 μmol) of the compound of Example22(b), the title compound was prepared. The reaction product was thenpurified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). It was then worked up in amanner similar to that described in Example 1(b), to give the titlecompound having 66 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M , pH 7.5; eluent B: acetonitrile; 10-60% B byvolume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample had a retention time of 18.22 minutes.

Ultraviolet Absorption Spectrum (H₂ O) λ_(max) nm: 255.

EXAMPLE 23 A Compound of Formula 23(a): ##STR48##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 115 mg (4 μmol) of the compound of Example21(b), the title compound was prepared. The reaction product waspurified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). It was then worked up in amanner similar to that described in Example 1(b), to give the titlecompound having 56 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample has a retention time of 18.38 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 24 24(a) A Compound of Formula 24(a): ##STR49##

Following a procedure similar to that described in Example 21(b), butusing 143 mg (5 μmol) of the compound of Example 21(a) andtriethylammonium5'-O-dimethoxytrityl-2-N-isobutyryl-2'-deoxyguanosine-3'-(4-chlorophenyl)phosphate(Methods Enzymol., 65, 610 (1980)!, the title compound was obtained.

24(b) A Compound of Formula 24(b): ##STR50##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (4 μmol) of the compound of Example24(a), the title compound was prepared. The reaction product waspurified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). It was then worked up in amanner similar to that described in Example 1(b), to give the titlecompound having 55 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample has a retention time of 18.55 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 25 DMT-O-TGGGAG-OH

The desired base sequence (5'-TGGGAG-3') was input to a 380B synthesizer(a product of Applied Biosystems Inc.), and a controlled pore glasscolumn (1 μmol scale) bounded with the corresponding nucleoside(2'-deoxyguanosine) at the 3'-terminal was connected to it. Thesynthesis was conducted on a scale of 1 μmol. The apparatus was set upnot to deprotect the DMT group after completion of the reaction, and theproduct having a DMT group was automatically freed from the resin, togive an oligodeoxyribonucleotide as an ammonia solution. This solutionwas sealed in a vial and heated at 55° C. for 8 hours, and the ammoniawas evaporated off in a stream of nitrogen. The resulting residue wasdissolved in a small amount of 0.1M TEAA (pH 7.0). This solution wasfiltered through a millipore-filter (0.2 μm), and the filtrate waspurified by reverse phase high performance liquid chromatography(Cosmosil 5C18-AR, 20×250 mm), under the conditions listed below.Fractions eluted after 13.5 minutes were collected and freed from thesolvent (acetonitrile) by distillation under reduced pressure followedby lyophilization, to give 800 μg of the title compound.

Elution time: 17.0 minutes

Conditions for preparative high performance liquid chromatography:

Buffer solution A: 0.1M triethylammonium

acetate buffer (pH 7.0);

Buffer solution B: 100% acetonitrile;

Flow rate; 9 ml/min.

    ______________________________________                                        Time (min)     Buffer A (%)                                                                            Buffer B (%)                                         ______________________________________                                         0             80        20                                                   15             55        45                                                   20             55        45                                                   ______________________________________                                    

EXAMPLES 26 TO 38

Following a procedure similar to that described in 25, the compounds ofExamples 26 through 38 were synthesized. The compound names and theirelution times are listed in Table 3.

                  TABLE 3                                                         ______________________________________                                        Example No.                                                                              Compound name      Retention time                                  ______________________________________                                        26         DMT--O--TGGG--OH   17.5 min                                        27         DMT--O--TGGGA--OH  16.7 min                                        28         DMT--O--TGGGG--OH  16.8 min                                        29         DMT--O--CGGGAGG--OH                                                                              16.3 min                                        30         DMT--O--TGGGAGG--OH                                                                              16.2 min                                        31         DMT--O--TTGGAGG--OH                                                                              18.0 min                                        32         DMT--O--TGCGAGG--OH                                                                              17.2 min                                        33         DMT--O--GGGGAGG--OH                                                                              15.3 min                                        34         DMT--O--mCGGGAGG--OH                                                                             16.3 min                                        35         DMT--O--mCGmCGAGG--OH                                                                            16.6 min                                        36         DMT--O--TTGGGAGG--OH                                                                             17.1 min                                        37         DMT--O--CTGGGAGG--OH                                                                             17.7 min                                        38         DMT--O--CTGGT--OH  17.2 min                                        39         DMT--O--CTGGC--OH  17.1 min                                        40         DMT--O--CTCGT--OH  17.6 min                                        41         DMT--O--CTCGC--OH  17.4 min                                        42         DMT--O--CTCGG--OH  17.5 min                                        43         DMT--O--CGGGT--OH  16.1 min                                        44         DMT--O--CGGGC--OH  16.1 min                                        45         DMT--O--CGGGG--OH  16.2 min                                        46         DMT--O--CGCGT--OH  17.8 min                                        47         DMT--O--CGCGC--OH  17.5 min                                        48         DMT--O--CGCGG--OH  18.0 min                                        49         DMT--O--TTGGA--OH  18.6 min                                        50         DMT--O--TTGGT--OH  18.6 min                                        51         DMT--O--TTGGC--OH  18.4 min                                        52         DMT--O--TTGGG--OH  17.7 min                                        53         DMT--O--TTCGA--OH  18.9 min                                        54         DMT--O--TTCGT--OH  18.7 min                                        55         DMT--O--TTCGC--OH  18.6 min                                        56         DMT--O--TTCGG--OH  18.8 min                                        57         DMT--O--TGGGT--OH  17.6 min                                        58         DMT--O--TGGGC--OH  17.4 min                                        59         DMT--O--TGCGA--OH  17.8 min                                        60         DMT--O--TGCGT--OH  17.7 min                                        61         DMT--O--TGCGC--OH  18.3 min                                        62         DMT--O--TGCGG--OH  17.6 min                                        63         DMT--O--CTCG--OH   17.9 min                                        64         DMT--O--TTCG--OH   19.1 min                                        65         DMT--O--CTGG--OH   17.1 min                                        66         DMT--O--CGCG--OH   18.2 min                                        67         DMT--O--TGCG--OH   18.0 min                                        68         DMT--O--CGGG--OH   16.2 min                                        69         DMT--O--TTGG--OH   18.2 min                                        70         DMT--O--GGGCGGGGC--OH                                                                            15.4 min                                        71         DMT--O--TAGGAGG--OH                                                                              17.7 min                                        72         DMT--O--TGGGAGGT--OH                                                                             16.2 min                                        73         DMT--O--TGGGCGCAG--OH                                                                            17.1 min                                        74         DMT--O--CCG--OH    16.7 min                                        75         DMT--O--TCGGAGG--OH                                                                              17.5 min                                        76         DMT--O--TGmCGAGG--OH                                                                             16.6 min                                        77         DMT--O--GTGGGAGG--OH                                                                             15.7 min                                        78         DMT--O--TGG--OH    15.4 min                                        79         DMT--O--TGGGAmGG   16.3 min                                        80         DMT--O--TGGGAGA--OH                                                                              16.7 min                                        81         DMT--O--AATGGGAGG--OH                                                                            14.9 min                                        ______________________________________                                    

EXAMPLE 82 82(a) A Compound of Formula 82(a): ##STR51##

The required reagents for synthesis as detailed below were supplied to acyclone (trade mark) Plus DNA/RNA synthesizer of Milligen/biosearch(Millipore Ltd., Japan). Also installed was a program cartridge for theamidite method (15 μmol). There were used an approximately 35 mMacetonitrile solution of5'-O-dimethoxytrityl-2-N-isobutyryl-2'-deoxyguanosine-3'-O-(methylN,N-diisopropylphosphoramidite) (Sigma) instead of the β-cyanoethylamidite corresponding to guanosine. By using an empty column (15.0 μmol)packed with 143 mg (5 μmol) of the compound of Example 21(a), inputtingthe base sequence GX to the synthesizer and working the program withoutacid treatment after bonding with a base, G, the title compound wasobtained.

82(b) A Compound of Formula 82(b): ##STR52##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (5 μmol) of the compound of Example82(a), the title compound was prepared. The product was purified bychromatography through a reverse phase silica gel column (PreparativeC18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50% acetonitrile; lineargradient; 254 nm). It was then worked up in a manner similar to thatdescribed in Example 1(b), to give the title compound having 66 OD (260nm) as an amorphous solid. Analysis by reverse phase high performanceliquid chromatography (Inertsil ODS, 6×250 mm; eluent A: 0.1M TEAA, pH7.5; eluent B: acetonitrile; 10-60% B by volume, 20 minutes; lineargradient; 1 ml/minute; 260 nm) showed that the sample has a retentiontime of 17.54 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 83 83(a) A Compound of Formula 83(a): ##STR53##

Following a procedure similar to that described in Example 82(a), butusing 143 mg (5 μmol) of the compound of Example 21(a), the titlecompound was prepared. In detail, after coupling with5'-O-dimethoxy-trityl-2-N-isobutyryl-2'-deoxyguanosine-3'-O-(methylN,N-diisopropyl)phosphoramidite, the column was taken away from theDNA/RNA synthesizer without oxidation by an oxidizing solution. 5 ml ofan acetonitrile solution of tetraethylthiuram disulfide (TETD) (AppliedBiosystems) were added to the column, and the column was allowed tostand at room temperature for 15 minutes. The column was then washedwith acetonitrile and installed in the synthesizer.

83(b) A Compound of Formula 83(b): ##STR54##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (5 μmol) of the compound of Example83(a), the title compound was prepared. The reaction product waspurified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 1 ml/minute; 260 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 111 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient, 1 ml/minute; 260 nm) showed thatthe sample has a retention time of 17.72 minute.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 84 84(a) A Compound of Formula 84(a): ##STR55##

The required reagents for synthesis as detailed below were supplied to aCyclone (trade mark) Plus DNA/RNA synthesizer of Milligen/biosearch(Millipore Ltd., Japan). Also installed was a program cartridge for theamidite method (15 μmol). There was used an approximately 35 mMtetrahydrofuran solution of deoxyguanosine (N-iBu) methylphosphonamidite (American Bionetic Inc.) instead of a β-cyanoethylamidite solution corresponding to guanosine. By using an empty column(15.0 μmol) packed with 143 mg (5 μmol) of the compound of Example 21(a)as a solid carrier, inputting a base sequence of GZ (in which Z is asdefined in Example 17) and working a program without acid treatmentafter bonding with a base G, the title compound was obtained.

84(b) A Compound of Formula 84(b): ##STR56##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (5 μmol) of the compound of Example84(a), the title compound was prepared. The reaction product waspurified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). It was then worked up in amanner similar to that described in Example 1(b), to give the titlecompound having 159 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample has a retention time of 18.03 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 85 85(a) A Compound of Formula 85(a): ##STR57##

Following a procedure similar to that described in Example 84(a), butusing a column packed with 143 mg (5 μmol) of the compound of Example21(a), the title compound was prepared. In more detail, after couplingwith deoxyguanosine (N-iBu)methyl phosphonamidite, the column wasremoved from the synthesizer without oxidation by an oxidizing solutionand then 5 ml of an acetonitrile solution of tetraethylthiuram disulfide(TETD) (Applied Biosystems) were added to the column. The column wasallowed to stand at room temperature for 15 minutes, after which it waswashed with acetonitrile and installed again in the synthesizer.

85(b) A Compound of Formula 85(b) ##STR58##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (5 μmol) of the compound of Example85(a), the title compound was prepared. The reaction product waspurified by chromatography through a reverse phase silica gel column(Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50%acetonitrile; linear gradient; 254 nm). It was then worked up in amanner similar to that described in Example 1(b), to give the titlecompound having 124 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample had a retention time of 18.07 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 86 A Compound of Formula 86(a): ##STR59##

Following a procedure similar to that described in Example 1(b), butusing a column packed with 143 mg (5 μmol) of the compound of Example21(a) and inputting the base sequence TGGGAGZ (in which Z is as definedin Example 17) to the DNA/RNA synthesizer described in Example 1(b), thetitle compound was prepared. The reaction product was purified bychromatography through a reverse phase silica gel column (PreparativeC18, Waters, 1.5×15 cm; 50 mM TEAB, pH 7.5; 20-50% acetonitrile; lineargradient; 254 nm). It was then worked up in a manner similar to thatdescribed in Example 1(b), to give the title compound having 54 OD (260nm) as an amorphous solid. Analysis by reverse phase high performanceliquid chromatography (Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAA, pH7.5; eluent B: acetonitrile; by volume, 15-65% 20 minutes; lineargradient; 1 ml/minute; 260 nm) showed that the sample had a retentiontime of 15.20 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 87 A Compound of Formula 87(a): ##STR60##

Following a procedure similar to that described in Example 86, but usinga column packed with 143 mg (5 μmol) of the compound of Example 21(a),the title compound was prepared. In more detail, after first couplingwith G-β-amidite at the 3'-terminal, the column was removed from theDNA/RNA synthesizer without oxidation by an oxidizing solution. 5 ml ofan acetonitrile solution of tetraethylthiuram disulfide (TETD) (AppliedBiosystems) were added to the column, and the column was allowed tostand at room temperature for 15 minutes, after which it was washed withacetonitrile and installed in the synthesizer.

The reaction product was purified by chromatography through a reversephase silica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB,pH 7.5; 20-50% acetonitrile; linear gradient; 254 nm). It was thenworked up in a manner similar to that described in Example 1(b), to givethe title compound having 136 OD (260 nm) as an amorphous solid.Analysis by reverse phase high performance liquid chromatography(Inertsil ODS, 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10-60% B by volume, 20 minute; linear gradient; 1ml/minute; 260 mm) showed that the sample had a retention time of 18.02minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 88 A Compound of Formula 88(a): ##STR61##

Dowex 50W-X2 ion-exchange resin (a trade mark for a product of DowChemical Co.; H-form; about 1 ml) was packed into a column, and 3 ml of20% v/v aqueous pyridine were passed through the column, which was thenwashed with water to prepare the pyridinium form of the resin in thecolumn. Following a similar procedure, but using 3 ml of a 1N aqueoussolution of sodium hydroxide, the sodium form of the resin was preparedin another column. The compound of Example 1(b) having 27 OD was appliedconsecutively to a combination of the pyridinium-form resin column andthe sodium-form resin column, in that order, and then the columns wereeluted with water, to give the title compound (a sodium salt) having 27OD (260 nm) as an amorphous solid. Analysis by reverse phase highperformance liquid chromatography (Inertsil ODS, 6×150 mm; eluent A:0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% B by volume, 20minutes; linear gradient; 1 ml/minute; 260 nm) showed that the samplehad a retention time of 18.12 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 256.

EXAMPLE 89 A Compound of Formula 89(a): ##STR62##

Dowex 50W-X2 ion-exchange resin (a trade mark for a product of DowChemical Co.; H-form; about 1 ml) was packed into a column, and 3 ml of20% v/v aqueous pyridine were passed through the column, which was thenwashed with water, to prepare a pyridinium form of the resin in thecolumn. Following a similar procedure, but using 3 ml of a 1N aqueoussolution of potassium hydroxide, a potassium form of the resin wasprepared in another column. The compound of Example 1(b) having 27 ODwas applied consecutively to a combination of the pyridinium-form resincolumn and the potassium-form resin column, and the columns were elutedwith water, to give the title compound (a potassium salt) having 27 OD(260 nm) as an amorphous solid. Analysis by reverse phase highperformance liquid chromatography (Inertsil ODS, 6×150 mm; eluent A:0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% B by volume, 20minute; linear gradient; 1 ml/minute; 260 nm) showed that the sample hada retention time of 18.18 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 90 A Compound of Formula 90(a) ##STR63##

Following a procedure similar to that described in Example 14(a), butusing 5'-O-(3,4-dibenzyloxybenzyl)-thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 10-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 119 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthis sample had a retention time of 19.20 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 91 A Compound of Formula 91(a): ##STR64##

Following a procedure similar to that described in Example 82(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 20-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 50 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthis sample had a retention time of 19.15 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 92 A Compound of Formula 92(a) ##STR65##

Following a procedure similar to that described in Example 22(c), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 67 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthis sample had a retention time of 19.51 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 93 A Compound of Formula 93(a): ##STR66##

Following a procedure similar to that described in Example 16(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 96 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M T pH 7.5; eluent B: acetonitrile; 10-60% B byvolume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthis sample had a retention time of 19.26 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 94 A Compound of Formula 94(a): ##STR67##

Following a procedure similar to that described in Example 12(c), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 97 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthis sample had a retention time of 19.16 minutes.

Ultraviolet Absorption spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 95 A Compound of Formula 95(a): ##STR68##

Following a procedure similar to that described in Example 23(a), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAS, pH7.5: 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 83 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample had a retention time of 19.80 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 96 A Compound of Formula 96(a): ##STR69##

A procedure similar to that described in Example 15(c) was repeated, butusing a column packed with 125 mg (5 μmol) of the compound of Example12(b) and inputting the base sequence XGGGGZ (in which Z is as definedin Example 17) to the synthesizer. The 90% v/v aqueous formamidesolution containing the title compound thus obtained was then heated at95° C. for 5 minutes. After this heating, the solution was cooledrapidly. The reaction mixture was then divided into four portions andeach was purified by reverse phase high performance liquidchromatography (Inertsil PREP-ODS 20.0×250 mm; eluent A: 0.1M TEAA pH7.0; eluent B: acetonitrile; 10 to 60% B by volume, 30 minutes; lineargradient; 7 ml/minute; 260 nm; column temperature 60° C.). Fractionseluted after 20.7 minutes were collected and worked up in a similarmanner to that described in Example 1(b), to give 79 OD (260 nm) of thetitle compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 253.

Retention time: 13.22 minutes High performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10 to 60% B by volume, 20 minutes; linear gradient; 1ml/minute; 260 nm)

EXAMPLE 97 A Compound of Formula 97(a): ##STR70##

A procedure similar to that described in Example 1(b) was repeated,except that a 35 mM acetonitrile solution of the compound of example15(b) in the amidite bottle X was used and the base sequence XGCGG wasinput to the synthesizer as a program. The 90% formamide aqueoussolution containing the title compound thus obtained was heated at 95°C. for 5 minutes. After this heating, the solution was cooled rapidly.The reaction mixture was then divided into four portions, and each waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS 20.0×250 mm; eluent A: 0.1M pH 7.0; eluent B:acetonitrile; 10 to 60% B by volume, 30 minutes; linear gradient; 7ml/minute; 260 nm; column temperature 60° C.). Fractions eluted after21.7 minutes were collected and worked up in a similar manner to thatdescribed in Example 1(b), to give 123 OD (260 nm) of the title compoundas an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 13.58 minutes high performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10 to 60% B by volume, 20 minutes, linear gradient; 1ml/minute; 260 nm).

EXAMPLE 98 A Compound of Formula 98(a): ##STR71##

Following a procedure similar to that described in Example 83(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 92 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 1 ml/minute; 260 nm) showed thatthe sample had a retention time of 19.46 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 99 A Compound of Formula 99(a): ##STR72##

Following a procedure similar to that described in Example 86, but using5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 43 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 260 nm) showed that the samplehad a retention time of 19.12 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

EXAMPLE 100 A Compound of Formula 100(a): ##STR73##

Following a procedure similar to that described in Example 87, but using5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; 50 mM TEAB, pH7.5; 15-50% acetonitrile; linear gradient; 254 nm). It was then workedup in a manner similar to that described in Example 1(b), to give thetitle compound having 36 OD (260 nm) as an amorphous solid. Analysis byreverse phase high performance liquid chromatography (Inertsil ODS,6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B: acetonitrile; 10-60% Bby volume, 20 minutes; linear gradient; 260 nm) showed that the samplehad a retention time of 19.11 minutes.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

EXAMPLE 101 A Compound of Formula 101(a): ##STR74##

Following a procedure similar to that described in Example 1(b), butusing a 35 mM acetonitrile solution of5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)! inthe amidite bottle X and inputting the base sequence XTGGGG to thesynthesizer as a program, the title compound was prepared. The reactionproduct was divided into three portions, and each was purified byreverse phase high performance liquid chromatography (Inertsil PREP-ODS,20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 25-55%B by volume, 30 minutes; linear gradient; 7 ml/minute; 254 nm).Fractions eluted after 19.8 minutes were collected and worked up in asimilar manner to that described in Example 1(b), to give 173.1 OD (260nm) of the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 15.1 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 2ml/minute; 254 nm).

EXAMPLE 102 A Compound of Formula 102(a): ##STR75##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(3,4-dibenzyloxybenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 7(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, and inputting the base sequence TGGGGGto the synthesizer as a program, the title compound was prepared. Thereaction product was divided into three portions and each was purifiedby reverse phase high performance liquid chromatography (InertsilPREP-ODS, 20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 25-55% B by volume, 30 minutes; linear gradient; 7ml/minute; 254 nm). Fractions eluted after 17.4 minutes were collectedand worked up in a similar manner to that described in Example 1(b), togive 120.2 OD (260 nm) of the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 13.1 minutes high performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 2ml/minute; 254 nm).

EXAMPLE 103 103(a) 5'-O- (Naphthalen-2-yl)methyl!thymidine

Following a procedure similar to that described in Example 6(a), butusing 442 mg (2 mmol) of 2-bromomethylnaphthalene, 253.1 mg (yield 33%)of the title compound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.12 (1H, broad singlet); 7.88-7.43 (8H, multiplet); 6.40 (1H, triplet,J=6.75 Hz); 4.76 (2H, singlet); 4.61-4.54 (1H, multiplet); 4.12-4.10(1H, multiplet); 3.88-3.72 (2H, multiplet); 2.40-2.20 (2H, multiplet);2.05 (1H, broad singlet); 1.58 (3H, singlet).

103(b) 5'-O- (Naphthalen-2-yl)methyl!thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 77 mg (0.2 mmol) of 5'-O- (naphthalen-2-yl)methyl!thymidineprepared as described in step (a) above!, 62.5 mg (yield 54%) of thetitle compound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.88-7.43 (8H, multiplet); 6.39 (1H, triplet, J=7.26 Hz); 4.75 (2H,broad singlet); 4.68-4.60 (1H, multiplet); 4.25, 4.20 (together 1H, twobroad singlets); 3.90-3.53 (6H, multiplet); 2.68-2.18 (4H, multiplet);1.57, 1.55 (together 3H, two singlets); 1.17 (12H, doublet, J=6.60 Hz).

103(c) A Compound of Formula 103(c): ##STR76##

Following a procedure similar to that described in Example 1(b), butusing 5'-O- (naphthalen-2-yl)methyl!thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was divided into three portions and each portion waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 7ml/minute; 254 nm). Fractions eluted after 12.8 minutes were collectedand worked up in a similar manner to that described in Example 1(b), togive of 257.5 OD (260 nm) the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 13.9 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 10-40% B by volume, 30 minutes; linear gradient; 2ml/minute; 254 nm).

EXAMPLE 104 104(a) 5'-O-(4-Phenylbenzyl)thymidine

Following a procedure similar to that described in Example 6(a), butusing 405 mg (2 mmol) of 4-phenylbenzyl chloride, 387.8 mg (yield 47%)of the title compound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃ +CD₃ OD, 4:1 v/v, TMS,270 MHz), δ ppm: 7.65-7.33 (10H, multiplet); 6.37 (1H, triplet, J=7.26Hz); 4.64 (2H, singlet); 4.55-4.48 (1H, multiplet); 4.13-4.09 (1H,multiplet); 3.87-3.70 (2H, multiplet); 2.38-2.15 (2H, multiplet); 1.63(3H, singlet).

104(b) 5'-O-(4-Phenylbenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 82 mg (0.2 mmol) of 5,-O-(4-phenylbenzyl)thymidine prepared asdescribed in step (a) above!, 71.8 mg (yield 59%) of the title compoundwere obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.62-7.34 (10H, multiplet); 6.40 (1H, triplet, J=6.60 Hz); 4.70-4.60(3H, multiplet); 4.27, 4.20 (together 1H, two broad singlets); 3.90-3.55(6H, multiplet); 2.67-2.57 (2H, multiplet); 2.53-2.16 (2H, multiplet);1.63 (3H, singlet); 1.19 (12H, doublet, J=6.60 Hz).

104(c) A Compound of Formula 104(c): ##STR77##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(4-Phenylbenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was divided into three portions and each portion waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1M p pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 7ml/minute; temperature 60° C.; 254 nm). Fractions eluted after 16.1minutes were collected and worked up in a similar manner to thatdescribed in Example 1(b), to give 281.8 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 7.1 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 2ml/minute; 60° C.; 254 nm).

EXAMPLE 105 105(a) 5'-O-(2-Phenylbenzyl)thymidine

Following a procedure similar to that described in Example 6(a), butusing 365 μl (2 mmol) of 2-phenylbenzyl bromide, 133.2 mg (yield 16%) ofthe title compound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.13 (1H, broad singlet); 7.50-7.28 (10H, multiplet); 6.34 (1H, triplet,J=6.75 Hz); 4.57, 4.50 (2H, two doublets, J=13.0 Hz); 4.30 (1H, broadsinglet); 3.98 (1H, broad singlet); 3.73-3.52 (2H, multiplet); 2.32-2.05(2H, multiplet); 1.90 (1H, broad singlet); 1.51 (3H, singlet).

105(b) 5'-O -(2-Phenylbenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 82 mg (0.2 mmol) of 5-O-(2-phenylbenzyl)thymidine prepared asdescribed in step (a) above!, 89.9 mg (yield 73%) of the title compoundwere obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.51-7.29 (10H, multiplet); 6.36 (1H, triplet, J=7.92 Hz); 4.55-4.45(3H, multiplet); 4.19, 4.11 (together 1H, two singlets); 3.90-3.52 (6H,multiplet); 2.66-2.54 (2H, multiplet); 2.45-2.03 (2H, multiplet); 1.51(3H, singlet); 1.19 (12H, doublet, J=6.60 Hz).

105(c) A Compound of Formula 105(c): ##STR78##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(2-phenylbenzyl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was divided into three portions and each portion waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 7ml/minute; 60° C.; 254 nm). Fractions eluted after 14.8 minutes werecollected and worked up in a similar manner to that described in Example1(b), to give 172.2 OD (260 nm) of the title compound as an amorphoussolid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 252.

Retention time: 6.1 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50- B by volume, 30 minutes; linear gradient; 2ml/minute; 60° C.; 254 nm).

EXAMPLE 106 106(a)3'-O-Triisopropylsilyl-5'-O-(4,4'-dimethoxytrityl)thymidine

1.485 g (2.73 mmol) of 5'-O-(4,4'-dimethoxytrityl)thymidine and 0.37 g(5.45 mmol) of imidazole were first dried by azeotropic distillationunder reduced pressure with pyridine and then dissolved in 6 ml ofdimethylformamide. 875 μl (4.09 mmol) of triisopropylsilyl chloride wereadded to this solution, and the resulting mixture was stirred overnightat room temperature. At the end of this time, 875 μl oftriisopropylsilyl chloride and 0.37 g of imisazole were added to themixture, which was then stirred for one day. The reaction mixture wasthen diluted with 100 ml of ethyl acetate and the diluted mixture waswashed twice, each time with 100 ml of a 5% w/v aqueous solution ofsodium hydrogencarbonate. The organic layer was dried over anhydroussodium sulfate and the solvent was removed by distillation under reducedpressure. The resulting residue was purified by column chromatographythrough 100 g of silica gel (70-230 mesh), using methylene chloridecontaining from 0 to 3% by volume of methanol as the eluent, to give1.861 g (yield 97%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.08 (1H, singlet); 7.67 (1H, singlet); 7.42-6.80 (13H, multiplet); 6.39(1H, triplet, J=5.94 Hz); 4.60-4.55 (1H, multiplet); 4.06-4.03 (1H,multiplet); 3.79 (6H, singlet); 3.53-3.26 (2H, multiplet); 2.42-2.18(2H, multiplet); 1.50 (3H, singlet); 1.03-0.90 (21H, multiplet).

106(b) 3'-O-(Triisopropylsilyl) thymidine

1.6 ml of trifluoroacetic acid were added dropwise to a solution of1.861 g (2.655 mmol) of3'-O-triisopropylsilyl-5'-O-(4,4'-dimethoxytrityl)thymidine prepared asdescribed in step (a) above! in 80 ml of chloroform, whilst cooling inan ice bath and stirring. The resulting mixture was stirred for 10minutes and then 2 ml of pyridine were added. The reaction mixture waswashed twice, each time with 100 ml of a 5% w/v aqueous solution ofsodium hydrogencarbonate and dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under reduced pressure, and theresulting residue was purified by column chromatography through 50 g ofsilica gel (70-230 mesh), using methylene chloride containing 4% byvolume of methanol as the eluent, to give 0.9965 g (yield 94%) of thetitle compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), 6 ppm:8.17 (1H, broad singlet); 7.36 (1H, singlet); 6.12 (1H, triplet, J=5.94Hz); 4.63-4.59 (1H, multiplet); 4.03-4.00 (1H, multiplet); 3.96-3.74(2H, multiplet); 2.48 (1H, broad singlet); 2.45-2.21 (2H, multiplet);1.91 (3H, singlet); 1.15-1.00 (21H, multiplet).

106(c) 3'-O-Triisopropylsilyl-5'-O- (4-benzyloxy)-benzyl!thymidine

88 mg (2 mmol) of sodium hydride (as a 55% w/w dispersion in mineraloil) were added to a solution of 398 mg (1 mmol) of3'-O-(triisopropylsilyl)thymidine prepared as described in step (b)above! in 2.5 ml of tetrahydrofuran, and the resulting mixture wasallowed to stand at 60° C. for 2 hours and then cooled to roomtemperature. 232 mg (1 mmol) of 4-benzyloxybenzyl chloride and 75 mg(0.5 mmol) of sodium iodide were added to the mixture, and the reactionmixture was then stirred overnight at room temperature and then at 55°C. for 8 hours. At the end of this time, the solvent was removed bydistillation under reduced pressure, and the residue was dissolved in100 ml of ethyl acetate. The resulting solution was washed twice, eachtime with 100 ml of 0.01N aqueous hydrochloric acid. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent was removedby distillation under reduced pressure. The resulting residue waspurified by column chromatography through 30 g of silica gel (230-400mesh), using methylene chloride containing from 1 to 2% by volume ofmethanol as the eluent, to give 237 mg (yield 40%) of the titlecompound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.00 (1H, broad singlet); 7.59 (1H, singlet); 7.48-6.90 (9H, multiplet);6.36 (1H, triplet, J=6.60 Hz); 5.07 (2H, singlet); 4.56-4.46 (1H,multiplet); 4.50 (2H, singlet); 4.07-4.03 (1H, multiplet); 3.80-3.60(2H, multiplet); 2.33-2.08 (2H, multiplet); 1.56 (3H, singlet);1.10-0.97 (21H, multiplet).

106(d) 5'-O- (4-Benzyloxy)benzyl thymidine

1.5 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoridewere added to a solution of 237 mg (0.4 mmol) of3'-O-triisopropylsilyl-5'-O- (4-benzyloxy)benzyl!thymidine (prepared asdescribed in step (c) above! in 1.5 ml of tetrahydrofuran, and theresulting mixture was stirred at room temperature for 3 hours. At theend of this time, the reaction mixture was freed from the solvent bydistillation under reduced pressure, and the resulting residue wasdissolved in 100 ml of ethyl acetate. This solution was washed twice,each time with 100 ml of a saturated aqueous solution of sodium chlorideand was then dried over anhydrous magnesium sulfate. The solvent wasremoved by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through 30 g of silica gel(230-400 mesh), using methylene chloride containing from 1 to 4% byvolume of methanol as the eluent, to give 108.5 mg (yield 61%) of thetitle compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.11 (1H, broad singlet); 7.56 (1H, singlet); 7.47-6.93 (9H, multiplet);6.38 (1H, triplet, J=7.26 Hz); 5.06 (2H, singlet); 4.57-4.47 (1H,multiplet); 4.52 (2H, singlet); 4.10-4.06 (1H, multiplet); 3.80-3.64(2H, multiplet); 2.38-2.15 (2H, multiplet); 1.67 (3H, singlet).

106(e) 5'-O- (4-Benzyloxy)benzyl!thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 88 mg (0.2 mmol) of 5'-O- (4-benzyloxy)benzyl!thymidine preparedas described in step (d) above!, 104.8 mg (yield 82%) of the titlecompound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.58, 7.56 (together 1H, two singlets); 7.46-6.93 (9H, multiplet); 6.37(1H, triplet, J=6.60 Hz); 5.06 (2H, singlet); 4.64-4.54 (1H, multiplet);4.60, 4.59 (2H, 2singlet); 4.25-4.15 (1H, multiplet); 3.90-3.50 (6H,multiplet); 2.66-2.54 (2H, multiplet); 2.50-2.10 (2H, multiplet); 1.65(3H, singlet); 1.18 (12H, doublet, J=7.26 Hz).

106(f) A Compound of Formula 106(f): ##STR79##

Following a procedure similar to that described in Example 1(b), butusing 5'-O- (4-benzyloxy)benzyl!-thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (e) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was synthesized. Thereaction product was divided into three portions and each portion waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 7ml/minute; 60° C.; 254 nm). Fractions eluted after 17.0 minutes werecollected and worked up in a similar manner to that described in Example1(b), to give 208.8 OD (260 nm) the title compound as an amorphoussolid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 8.1 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; aqueous solution of 0.1M TEAA, pH 7.3;eluent B: acetonitrile; 20-50% B by volume, 30 minutes, linear gradient;2 ml/minute; 60° C.; 254 nm).

EXAMPLE 107 107(a) 5'-O-(9-Phenylxanthen-9-yl)thymidine

585 mg (2 mmol) of 9-chloro-9-phenylxanthene were added to a solution of484 mg (2 mmol) of thymidine in 20 ml of pyridine, and the resultingmixture was stirred at room temperature for 1 hour whilst shading itfrom light. The reaction mixture was then diluted with 200 ml ofmethylene chloride, and the diluted mixture was washed twice, each timewith 200 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate.The organic layer was dried over anhydrous sodium sulfate, and thesolvent was removed by distillation under reduced pressure. The residuewas purified by column chromatography through 35 g of silica gel (70-230mesh), using methylene chloride containing from 0 to 2.5% by volume ofmethanol as the eluent, to give 647.8 mg (yield 65%) of the titlecompound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.33 (1H, broad singlet); 7.62 (1H, singlet); 7.45-7.02 (13H,multiplet); 6.36 (1H, triplet, J=5.94 Hz); 4.49-4.41 (1H, multiplet);4.02-3.96 (1H, multiplet); 3.29-3.12 (2H, multiplet); 2.52-2.24 (2H,multiplet); 1.99 (1H, doublet, J=3.96 Hz); 1.67 (3H, singlet).

107(b) 5'-O-(-9-Phenylxanthen-9-yl)thymidine 2-cyanoethylN-N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 100 mg (0.2 mmol) of 5'-O-(9-phenylxanthen-9-yl)thymidine preparedas described in step (a) above!, 134.9 mg (yield 99%) of the titlecompound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.03 (1H, broad singlet); 7.69, 7.64 (together 1H, two singlets);7.40-7.03 (13H, multiplet); 6.40-6.32 (1H, multiplet); 4.58-4.47 (1H,multiplet); 4.15-4.05 (1H, multiplet); 3.90-3.10 (6H, multiplet);2.82-2.28 (4H, multiplet); 1.63, 1.62 (together 3H, two singlets); 1.16(12H, doublet, J=6.6 Hz).

107(c) A Compound of Formula 107(c): ##STR80##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(9-phenylxanthen-9-yl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was synthesized. Thereaction product was divided into three portions and each portion waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 7ml/minute; 60° C.; 254 nm). Fractions eluted after 19.7 minutes werecollected and worked up in a similar manner to that described in Example1(b), to give 145.6 OD (260 nm) of the title compound as an amorphoussolid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 249.

Retention time: 10.9 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEA., pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 2ml/minute; 60° C.; 254 nm).

EXAMPLE 108 108(a) 5'-O-(9-Phenylfluoren-9-yl)thymidine

770 mg (2.4 mmol) of 9-bromo-9-phenylfluorene were added to a solutionof 242 mg (1 mmol) of thymidine in 10 ml of pyridine, and the resultingmixture was stirred at 100° C. for 8 hours. At the end of this time, thereaction mixture was concentrated by evaporation under reduced pressure,and the concentrate was dissolved in 100 ml of methylene chloride. Thesolution was washed with 100 ml of a 5% w/v aqueous solution of sodiumhydrogencarbonate and dried over anhydrous sodium sulfate. The solventwas removed by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through 30 g of silica gel(230-400 mesh), using methylene chloride containing from 1 to 3% byvolume of methanol as the eluent, to give 194.2 mg (yield 37%) of thetitle compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.06 (1H, broad singlet); 7.76 (1H, singlet); 7.72-7.20 (13H,multiplet); 6.41 (1H, triplet, J=6.60 Hz); 4.64-4.58 (1H, multiplet);3.95-3.90 (1H, multiplet); 3.49-3.13 (2H, multiplet); 2.45-2.38 (2H,multiplet); 1.88 (1H, doublet, J=3.96 Hz); 1.48 (3H, singlet).

108(b) 5'-O-(9-Phenylfluoren-9-yl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 105 mg (0.2 mmol) of 5'-O-(9-phenylfluoren-9-yl)thymidine preparedas described in step (a) above!, 110.8 mg (yield 76%) of the titlecompound were obtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.00 (1H, broad singlet); 7.80 (1H, singlet); 7.78-7.20 (13H,multiplet); 6.44-6.37 (1H, multiplet); 4.72-4.62 (1H, multiplet);4.10-4.00 (1H, multiplet); 3.90-3.10 (6H, multiplet); 2.75-2.34 (4H,multiplet); 1.46, 1.45 (together 3H, two singlets); 1.18 (12H, doublet,J=6.60 Hz).

108(c) A Compound of Formula 108(c): ##STR81##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(9-phenylfluoren-9-yl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was synthesized. Thereaction product was divided into three portions and each portion waspurified by reverse phase high performance liquid chromatography(Inertsil PREP-ODS, 20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-505 B by volume, 30 minutes; linear gradient; 7ml/minute; 60° C.; 254 nm). Fractions eluted after 19.1 minutes werecollected and worked up in a similar manner to that described in Example1(b), to give 291.2 OD (260 nm) of the title compound as an amorphoussolid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 10.4 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 2ml/minute; 60° C.; 254 nm).

EXAMPLE 109 109(a) 5'-(S-Triphenylmethyl)-thio-5'-deoxythymidine2-cyanoethyl N,N-diisopropylphosphoramidite

Following a procedure similar to that described in Example 11(b), butusing 100 mg (0.2 mmol) of 5'-(S-triphenylmethyl)thio-5'-deoxythymidineB. S. Sproate, B. Beijer, P. Rider, P. Neuner, Nucleic Acids Res., 15,(12) 4837 (1987)!, 88 mg (yield 62%) of the title compound wereobtained.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.45-7.18 (16H, multiplet); 6.23-6.17 (1H, multiplet); 4.31-4.20 (1H,multiplet); 4.11-4.00 (1H, multiplet); 3.85-3.43 (4H, multiplet);2.62-1.98 (4H, multiplet); 1.56 (3H, singlet); 1.20-1.05 (12H,multiplet).

109(b) A Compound of Formula 109(b): ##STR82## M&C FOLIO: 69128/FP-9403WANGDOC: 2384H

Following a procedure similar to that described in Example 1(b), butusing 5'-(S-triphenylmethyl)thio-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (a) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was synthesized. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×15 cm; eluent A: 50 mMTEAB, pH 7.5; eluent B: acetonitrile; 20-50% B by volume, lineargradient; 254 nm). It was then worked up in a similar manner to thatdescribed in Example 1(b), to give 122.3 OD (260 nm) of the titlecompound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O) λ_(max) nm: 254.

Retention time: 19.0 minutes high performance liquid chromatography(Inertsil ODS, 6×150 mm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10-60% B by volume, 20 minutes; linear gradient; 1ml/minute; 60° C.; 260 nm).

EXAMPLE 110 A Compound of Formula 110(a): ##STR83##

Following a procedure similar to that described in Example 1(b), butusing 5'-O-(9-phenylfluoren-9-yl)thymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in Example 108(b)!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite and inputting the base sequence TGGGG toa synthesizer, the title compound was prepared. The reaction product wasdivided into three portions and each portion was purified by reversephase high performance liquid chromatography (Inertsil PREP-ODS,20.0×250 mm; eluent A: 0.1M TEAA, pH 7.3; eluent B: acetonitrile; 25-55%B by volume, 30 minutes; linear gradient; 7 ml/minute; 60° C.; 254 nm).Fractions eluted after 14.6 minutes were collected and worked up in asimilar manner to that described in Example 1(b), to give 28.3 OD (260nm) of the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O) λ_(max) nm: 256.

Retention time: 10.7 minutes High performance liquid chromatography(YMC-Pack A-312, S-5, 120A, ODS; eluent A: 0.1 M TEAA, pH 7.3; eluent B:acetonitrile; 20-50% B by volume, 30 minutes; linear gradient; 2ml/minute; 60° C.; 254 nm).

EXAMPLE 111 A Compound of Formula 111(a): ##STR84##

A procedure similar to that described in Example 15(c) was repeated, butusing a column packed with 125 mg (5 μmol) of the compound of Example12(b) and inputting the base sequence XGCGGZ (in which Z is as definedin Example 17) to the DNA/RNA synthesizer described in Example 1(b). The90% aqueous formamide solution containing the title compound thusobtained was heated at 95° C. for 5 minutes. After this heating, thesolution was cooled rapidly. The reaction mixture was divided into fourportions and each was purified by reverse phase high performance liquidchromatography (Inertsil PREP-ODS 20.0×250 mm; eluent A: 0.1M TEAA pH7.0; eluent B: acetonitrile; 10 to 60% B by volume, 30 minutes; lineargradient; 7 ml/minute; 260 nm; column temperature 60° C.). Fractionseluted after 20.8 minutes were collected and worked up in a similarmanner to that described in Example 1(b), to give 82 OD (260 nm) of thetitle compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time: 13.38 minutes High performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10 to 60% B by volume, 20 minutes, linear gradient; 1ml/minute; 260 nm).

EXAMPLE 112 112(a) 5'- (3.4-dibenzyloxy)benzylthiol-5'-deoxythymidine

258 mg (1 mmol) of 5'-deoxy-5'-mercaptothymidine was added to 20 ml ofacetone. 406 mg (1.2 mmol) of 3,4-dibenzyloxybenzyl chloride and 1 g ofanhydrous potassium carbonate were then added to the solution under anatmosphere of nitrogen. The resulting mixture was stirred whilst beingheated under reflux for 1 hour. At the end of this time, precipitateswere filtered off from the reaction mixture, and the filtrate was freedfrom the solvent by distillation under reduced pressure. The residue wasdissolved a small amount of methylene chloride and purified by columnchromatography through 10 g of of silica gel using a 5:95 by volumemixture of methanol and methylene chloride as the eluent, to give 452 mgof the title compound as a colorless caramel-like residue. This residuewas lyophilized from benzene, to give 180 mg (yield 32%) of the titlecompound as white crystals. ¹ H Nuclear Magnetic Resonance Spectrum(CDCl₃, 270 MHz, TMS), δ ppm: 8.26 (1H, broad singlet); 6.78-7.46 (14H,multiplet); 6.20 (1H, triplet, J=6.6 Hz); 5.15 & 5.17 (together 4H, twosinglets); 4.20-4.27 (1H, multiplet); 3.87-3.91 (1H, multiplet);3.67-3.68 (2H, multiplet); 2.61-2.70 (2H, multiplet); 2.09-2.40 (2H,multiplet); 1.91-1.92 (3H, multiplet).

112(b) 5'- (3.4-Dibenzyloxy)benzylthiol-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite

112 mg (0.2 mmol) of 5'-((3,4-dibenzyloxy)benzylthiol-5'-deoxythymidineprepared as described in step (a) above! were dried by azeotropicdistillation with pyridine and then dissolved in 1 ml of methylenechloride. 17 mg (0.1 mmol) of diisopropylammonium tetrazolide were thenadded to the solution. 70 μl (0.22 mmol) of 2-cyanoethylN,N,N',N'-tetraisopropylphosphorodiamidite were then added dropwise tothe mixture, under an atmosphere of argon. The resulting mixture wasstirred at room temperature for 3 hours under the same atmosphere. Themethylene chloride was then removed by distillation under reducedpressure. The resulting residue was dissolved in 10 ml of ethyl acetate,and the solution was washed with a 10% w/v aqueous solution of sodiumcarbonate and with a saturated aqueous solution of sodium chloride, inthat order. The solution was then dried over anhydrous sodium sulfate,after which the solvent was removed by distillation under reducedpressure, and the resulting residue was purified by columnchromatography through 10 g of silica gel (70-230 mesh), using ethylacetate as the eluent, to give 115 mg (yield 76%) of the title compoundas a caramel-like substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.16 (1H, broad singlet); 6.76-7.45 (14H, multiplet); 6.23-6.29 (1H,multiplet); 5.14-5.16 (4H, multiplet); 4.38-4.46 (1H, multiplet);4.08-4.16 (1H, multiplet); 3.50-3.90 (6H, multiplet); 2.09-2.80 (6H,multiplet); 1.91-1.93 (3H, multiplet); 1.08-1.58 (12H, multiplet).

112(c) A Compound of Formula 112(c): ##STR85##

Following a procedure similar to that described in Example 1(b), butusing 5'- (3,4-dibenzyloxy)benzylthiol-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×150 mm; eluent A: 50 mMaqueous triethyl ammonium hydrogencarbonate buffer (TEAB); pH 7.5;eluent B: acetonitrile; 15 to 50% B by volume; linear gradient; 260 nm).The eluted fractions containing the title compound were collected andworked up in a similar manner to that described in Example 1(b), to give57 OD (260 mm) of the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 253.

Retention time: 16.85 minutes High performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10 to 60% B by volume, 20 minutes; linear gradient; 1ml/minute; 260 nm).

EXAMPLE 113 113(a) 5'- (Anthracen-9-yl)methylthiol-5'-deoxythymidine

258 mg (1 mmol) of 5'-deoxy-5'-mercaptothymidine was added to 20 ml ofacetone. 272 mg (1.2 mmol) of 9-chloromethylanthracene and 1 g ofanhydrous potassium carbonate were then added to the solution under anatmosphere of nitrogen. The resulting mixture was then stirred whilstbeing heated under reflux for 2 hours. At the end of this time,precipitates were filtered off from the reaction mixture, and thefiltrate was freed from the solvent by distillation under reducedpressure. The residue was crystallized from 10 ml of ethanol, to give156 mg (yield 35%) of the title compound as pale yellow crystals.

¹ H Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethylsulfoxide, 270 MHz, TMS), δ ppm: 8.56 (1H, singlet); 8.40 (2H, doublet,J=8.7 Hz); 8.09 (2H, doublet, J=8.2 Hz); 7.51-7.61 (5H, multiplet);6.24-6.28 (1H, multiplet); 5.43 (1H, broad singlet); 4.87-4.89 (2H,multiplet); 4.24-4.25 (1H, triplet, J=2.7 Hz); 4.03-4.07 (1H,multiplet); 3.05 (2H, doublet, J=6.5 Hz); 2.07-2.29 (2H, multiplet);1.72-1.73 (3H, multiplet).

113(b) 5'- (Anthracen-9-yl)methylthiol-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite

74 mg (0.165 mol) of 5'- (anthracen-9-yl)methylthio!-5'-deoxythymidineprepared as described in step (a) above! were dried by azeotropicdistillation with pyridine and then dissolved in 1 ml oftetrahydrofuran. 0.115 ml (0.659 mmol) of N,N-diisopropyl-N-ethylaminewas added to the solution. 49 μl (0.22 mmol) of 2-cyanoethylN,N-diisopropylchlorophosphoramidite were then added dropwise to themixture, under an atmosphere of argon. The resulting mixture was stirredat room temperature for 1.75 hours under the same atmosphere. Thetetrahydrofuran was then removed by distillation under reduced pressure.The resulting residue was dissolved in 10 ml of ethyl acetate, and thesolution was washed with a 10% w/v aqueous solution of sodium carbonateand with a saturated aqueous solution of sodium chloride, in that order.The solution was dried over anhydrous sodium sulfate, and then thesolvent was removed by distillation under reduced pressure, and theresidue was purified by column chromatography through 10 g of silica gel(70-230 mesh), using ethyl acetate as the eluent, to give 85 mg (yield79%) of the title compound as a foam-like substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.26-8.43 (10H, multiplet); 6.26-6.33 (1H, multiplet); 4.74-4.93 (2H,multiplet); 4.32-4.42 (1H, multiplet); 4.20-4.28 (1H, multiplet);3.49-3.80 (4H, multiplet); 2.89-3.11 (2H, multiplet); 1.93-2,68 (4H,multiplet); 1.71-1.76 (3H, multiplet); 1.08-1.22 (12H, multiplet).

113(c) A Compound of Formula 113(c): ##STR86##

Following a procedure similar to that described in Example 1(b), butusing 5'- (anthracen-9-yl)methylthiol-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite (prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×150 mm; eluent A: 50 mMTEAB; pH 7.5; eluent B: acetonitrile; 15 to 50% B by volume; lineargradient; 260 nm). The eluted fractions containing the title compoundwere collected and worked up in a similar manner to that described inExample 1(b), to give 30 OD (260 nm) of the title compound as anamorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 255.

Retention time: 13.52 minutes High performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10 to 60% B by volume, 20 minutes, linear gradient; 1ml/minute; 260 nm).

EXAMPLE 114 114(a) 5'- (2-Naphthyl)methylthiol-5'-deoxythymidine

258 mg (1 mmol) of 5'-deoxy-5'-mercaptothymidine was added to 20 ml ofacetone. 265 mg (1.2 mmol) of 2-bromomethylnaphthalene and 1 g ofanhydrous potassium carbonate were then added to the solution under anatmosphere of argon. The resulting mixture was stirred whilst beingheated under reflux for 2 hours. At the end of this time, precipitateswere filtered off from the reaction mixture, and the filtrate was freedfrom the solvent by distillation under reduced pressure. The residue wascrystallized from 10 ml of ethanol, to give 100 mg (yield 25%) of thetitle compound as white crystals.

¹ H Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethylsulfoxide, 270 MHz, TMS), δ ppm: 7.84-7.90 (1H, broad singlet); 7.78(1H, singlet); 7.46-7.53 (4H, multiplet); 6.16-6.19 (1H, multiplet);5.34 (1H, doublet, J=4.4 Hz); 4.14-4.19 (1H, multiplet); 3.92-3.99 (2H,multiplet); 3.83-3.87 (1H, multiplet); 2.62-2.78 (2H, multiplet);2.02-2.23 (2H, multiplet); 1.75-1.79 (3H, multiplet).

114(b) 5'- (2-Naphthyl)methylthiol-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite

79.7 mg (0.2 mmol) of 5'-((2-naphthyl)methylthio!-5'-deoxythymidine(prepared as described in step (a) above! were dried by azeotropicdistillation with pyridine and then dissolved in 2.5 ml oftetrahydrofuran. 0.084 ml (0.48 mmol) of diisopropylamine was then addedto the solution. 54 μl (0.24 mmol) of 2-cyanoethylN,N-diisopropylchlorophosphoramidite were then added dropwise to themixture, under an atmosphere of argon. The resulting mixture was stirredat room temperature for 1.75 hours under the same atmosphere. Thetetrahydrofuran was then removed by distillation under reduced pressure.The resulting residue was dissolved in 10 ml of ethyl acetate, and thesolution was washed with a 10% w/v aqueous solution of sodium carbonateand with a saturated aqueous solution of sodium chloride, in that order.The solution was then dried over anhydrous magnesium sulfate, afterwhich the solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography through 10 g of silica gel(70-230 mesh), using ethyl acetate as the eluent, to give 67 mg (yield56%) of the title compound as a foam-like substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:8.32 (1H, broad singlet); 7.26-7.85 (8H, multiplet); 6.27 (1H,multiplet); 4.38-4.46 (1H, multiplet); 4.11-4.19 (1H, multiplet);3.93-3.95 (2H, multiplet); 3.47-3.90 (4H, multiplet); 2.10-2.88 (6H,multiplet); 1.62-1.90 (3H, multiplet); 1.10-1.21 (12H, multiplet).

114(c) A Compound of Formula 114(c) ##STR87##

Following a procedure similar to that described in Example 1(b), butusing 5'- (2-naphthyl)methylthiol-5'-deoxythymidine 2-cyanoethyl N,N-diisopropylphosphoramidite prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasesilica gel column (Preparative C18, Waters, 1.5×150 mm; eluent A: 50 mMTEAB; pH 7.5; eluent B: acetonitrile; 15 to 50% B by volume; lineargradient; 260 nm). The eluted fractions containing the title compoundwere collected and worked up in a similar manner to that described inExample 1(b), to give 165 OD (260 nm) of the title compound as anamorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 254.

Retention time : 12.07 minutes High performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 10 to 60% B by volume, 20 minutes, linear gradient; 1ml/minute; 260 nm).

EXAMPLE 115 115(a) 5'-{3,5-Bis 3,5-(dibenzyloxy)benzyloxy!benzylthio}-5'-deoxythymidine

258 mg (1 mmol) of 5'-deoxy-5'-mercaptothymidine was added to 20 ml ofacetone. 969 mg (1.2 mmol) of 3,5-bis(3,5-(dibenzyloxy)benzyloxy!benzylbromide and 1 g of anhydrous potassium carbonate were then added to thesolution under an atmosphere of argon. The resulting mixture was stirredwhilst being heated under reflux for 2 hours. At the end of this time,precipitates were filtered off from the reaction mixture, and thefiltrate was freed from the solvent by distillation under reducedpressure. The residue was lyophilized from benzene, to give 365 mg(yield 37%) of the title compound as a white powder.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.99 (1H, broad singlet); 7.23-7.42 (21H, multiplet); 6.49-6.68 (9H,multiplet); 4.98-5.03 (12H, multiplet); 4.18-4.26 (1H, multiplet);3.87-3.91 (1H, multiplet); 3.64-3.71 (2H, multiplet); 2.67 (2H, doublet,J=5.7 Hz); 2.00-2.64 (2H, multiplet); 1.86-1.92 (3H, multiplet).

115(b) 5'-{3,5-Bis3,5-(dibenzyloxy)benzyloxy!benzylthio!-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite

197 mg (0.2 mmol) of 5'-{3,5-bis3,5-(dibenzyloxy)benzyloxylbenzylthio}-5'-deoxythymidine (prepared asdescribed in step (a) above! were dried by azeotropic distillation withpyridine and then dissolved in 1 ml of methylene chloride. 0.017 g (0.1mmol) of diisopropylammonium tetrazolide was then added to the solution.70 μl (0.22 mmol) of 2-cyanoethylN,N,N',N'-tetraisopropylphosphorodiamidite were then added dropwise tothe mixture, under an atmosphere of argon. The resulting mixture wasstirred at room temperature for 3 hours under the same atmosphere. Thetetrahydrofuran was then removed by distillation under reduced pressure.The resulting residue was dissolved in 10 ml of ethyl acetate, and thesolution was washed with a 10% w/v aqueous solution of sodium carbonateand with a saturated aqueous solution of sodium chloride, in that order.The solution was then dried over anhydrous magnesium sulfate, afterwhich the solvent was removed by distillation under reduced pressure,and the residue was purified by column chromatography through 10 g ofsilica gel (70-230 mesh), using ethyl acetate as the eluent, to give 103mg (yield 43%) of the title compound as a caramel-like substance.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.27-7.44 (20H, multiplet); 6.51-6.69 (10H, multiplet); 4.98-5.05 (12H,multiplet); 4.44-4.51 (1H, multiplet); 4.13-4.18 (1H, multiplet);3.47-3.87 (6H, multiplet); 2.17-2.84 (6H, multiplet); 1.92 (3H,singlet); 1.08-1.34 (12H, multiplet);

115(c) A Compound of Formula 115(c): ##STR88##

Following a procedure similar to that described in Example 1(b), butusing 5'-{3,5-bis 3,5-(dibenzyloxy)-benzyloxy!benzylthio!-5'-deoxythymidine 2-cyanoethylN,N-diisopropylphosphoramidite (prepared as described in step (b) above!instead of the 5'-O-tritylthymidine 2-cyanoethylN,N-diisopropylphosphoramidite, the title compound was prepared. Thereaction product was purified by chromatography through a reverse phasehigh performance liquid chromatography (Inertsil PREP-ODS 20.0×250 mm;eluent A: 0.1M TEAA pH 7.0; eluent B: acetonitrile; 30 to 100% B byvolume, 30 minutes; linear gradient; 7 ml/minute; 260 nm columntemperature 60° C.). Fractions eluted after 26.5 minutes were collectedand worked up in a similar manner to that described in Example 1(b), togive 86 OD (260 nm) of the title compound as an amorphous solid.

Ultraviolet Absorption Spectrum (H₂ O), λ_(max) nm: 257.

Retention time: 18.44 minutes High performance liquid chromatography(Inertsil ODS-2; 6×150 nm; eluent A: 0.1M TEAA, pH 7.5; eluent B:acetonitrile; 40 to 100% B by volume, 25 minutes, linear gradient; 1ml/minute; 260 nm).

PREPARATIONS

The following Preparations illustrate the preparation of alternativestarting materials for the preparation of the compounds of the presentinvention.

Preparation 1 2- 2-O-(4,4'-Dimethoxytrityloxy)ethylsulfonyl!-ethylmonosuccinate

1.37 g (3.0 mmol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethanol (Tetrahedron Lett.27, 4705 (1986)! was dried by azeotropic distillation under reducedpressure with pyridine and then dissolved in 12 ml of methylenechloride. 315 mg (3.15 mmol) of succinic anhydride and 384 mg (3.15mmol) of 4-(dimethylamino)pyridine were added to the resulting solution,which was then stirred for 30 minutes. After the completion of thereaction had been confirmed by thin layer chromatography, 80 ml ofmethylene chloride were added to the reaction mixture. The resultingmixture was then washed with a 0.5M aqueous solution of potassiumdihydrogen phosphate (pH 5.0) and with water, in that order, and theorganic layer was dried over anhydrous anhydrous sodium sulfate. Thesolvent was then removed by distillation under reduced pressure, to give1.60 g (yield 96%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.40-6.83 (13H, multiplet); 4.58-4.53 (2H, triplet, J=5.94 Hz); 3.79(6H, singlet); 3.68-3.64 (2H, triplet, J=5.61 Hz); 3.50-3.45 (2H,triplet, J=5.94 Hz); 3.18-3.14 (2H, triplet, J=5.61 Hz); 2.71-2.61 (4H,multiplet).

Preparation 2 A Compound of Formula 2 (p): ##STR89##

1.60 g (2.87 mmol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethyl monosuccinate (preparedas described in Preparation 1) were dissolved in 18 ml ofdimethylformamide, and 0.96 g (3.6 mmol) of pentachlorophenol and 0.96 g(4.5 mmol) of 1,3-dicyclohexylcarbodiimide were added to the resultingsolution, which was then stirred for 18 hours. The insolubles whichprecipitated were separated by filtration, and the solvent was removedfrom the filtrate by evaporation under reduced pressure. Benzene wasadded to the residue, and further insolubles which precipitated wereseparated by filtration. The solvent was again removed from the filtrateby evaporation under reduced pressure.

The residue (0.16 g, 0.2 mmol) was dissolved in 4 ml ofdimethylformamide, and 15 μl (0.11 mmol) of triethylamine and 1.0 g ofaminopropyl-CPG (85.7 μmol/g of amino groups are introduced thereto)were added to the solution, which was then left to stand at roomtemperature for 24 hours. At the end of this time, the CPG carrier wascollected by filtration, washed with methylene chloride and then driedunder by evaporation reduced pressure. 5 ml each of Cap A and Bsolutions (Nippon Millipore Limited) were added to the CPG carrier, andthe mixture was left to stand for 5 minutes. The mixture was then washedwith pyridine and with methylene chloride, in that order, and dried byevaporation under reduced pressure, to give the title compound.

The amount of the compound of Preparation 1 introduced into the titlecompound was determined according to the following method. A deblocksolution (a 3% by volume solution of dichloroacetic acid in methylenechloride, Nippon Millipore Limited) was added to 11.4 mg of the titlecompound, and the mixture was shaken for 3 minutes, after whichsufficient methylene chloride was added to make up the total amount to20 ml. 0.4 ml of the solvent was distilled off, and then 3 ml of a 3:2by volume solution of perchloric acid in ethanol was added to theresidue, and the absorbance of the dimethoxytrityl cation at 500 nm wasmeasured (ε=71700).

The amount of dimethoxytrityl groups introduced was 53.1 μmol/g.

Preparation 3 2- 2-O-(4,4'-Dimethoxytrityloxy)ethylsulfonyl!-ethyl2,2,2-trichloroethoxycarbonate

1.1 g (2.4 mmol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethanol Tetrahedron Lett. 27,4705 (1986)! were dried by azeotropic distillation under reducedpressure with pyridine and then dissolved in 12 ml of methylenechloride. 0.35 ml (2.6 mmol) of 2,2,2-trichloroethoxycarbonyl chloridewas added to the solution, which was then stirred for 2 hours. After thecompletion of the reaction had been confirmed by thin layerchromatography, the reaction mixture was poured into a mixture of 100 mlof methylene chloride and 100 ml of a 5% w/v aqueous solution of sodiumhydrogencarbonate to effect phase separation. The organic layers werewashed with a 5% w/v aqueous solution of sodium hydrogencarbonate, andthey were then collected and dried over anhydrous sodium sulfate. Thesolvent was then removed by distillation under reduced pressure, and theresidue was purified by reverse phase column chromatography (PreparativeC18, Waters, 2.2×7.0 cm, solvent: 60% v/v aqueous acetonitrile), to give1.35 g (yield 89%.) of the title compound as an amorphous powder.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.41-6.83 (13H, multiplet); 4.75 (2H, singlet); 4.70-4.66 (2H, triplet,J=5.94 Hz); 3.80 (6H, singlet); 3.68-3.64 (2H, triplet, J=5.28 Hz);3.61-3.56 (2H, triplet, J=6.27 Hz); 3.23-3.19 (2H, triplet, J=5.28 Hz).

Preparation 4 A Compound of Formula 4(p): ##STR90##

0.126 g (0.2 mmol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethyl2,2,2-trichloroethoxycarbonate (prepared as described in Preparation 3)was dissolved in 5 ml of dimethylformamide, and 15 μl (0.11 mmol) oftriethylamine and 1.0 g of aminopropyl-CPG (85.7 μmol/g of amino groupsare introduced thereto) were added to the resulting solution and washedwith a 1% v/v solution of triethylamine in dimethylformamide. Themixture was then left to stand at room temperature for 4 days. At theend of this time, the CPG carrier was collected by filtration and washedwith methylene chloride, after which it was dried by evaporation underreduced pressure. 5 ml each of Cap A and B solutions (Nippon MilliporeLimited) were added to the CPG carrier, and the mixture was left tostand for 5 minutes. The mixture was then washed with pyridine and withmethylene chloride, in that order, and dried by evaporation underreduced pressure, to give the title compound.

The amount of the compound of Preparation 3 introduced into the titlecompound was determined according to the following method. A deblocksolution (a 3% v/v solution of dichloroacetic acid in methylenechloride, Nippon Millipore Limited) was added to 11.4 mg of the titlecompound, and the mixture was shaken for 3 minutes, after whichsufficient methylene chloride was added to make up a total amount of 20ml. 0.4 ml of the solvent was distilled off, and then 3 ml of a 3:2 byvolume solution of perchloric acid in ethanol were added to the residue,and the absorbance of the dimethoxytrityl cation at 500 nm was measured(ε=71700).

The amount of dimethoxytrityl groups introduced was 24.0 μmol/g.

Preparation 5 A Compound of Formula 5(p): ##STR91##

1.60 g (2.87 mmol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethyl monosuccinate (preparedas described in Preparation 1) were dissolved in 18 ml ofdimethylformamide, and 0.96 g (3.6 mmol) of pentachlorophenol and 0.96 g(4.5 mmol) of 1,3-dicyclohexylcarbodiimide were added to the solution.The resulting mixture was then stirred at room temperature for 18 hours.At the end of this time, precipitates were filtered off from thereaction mixture, and the filtrate was free from the solvent bydistillation under reduced pressure. Benzene was added to the residue.The resulting precipitates were filtered off, and the filtrate was againfreed from the solvent by distillation under reduced pressure. 1.0 g(0.92 mmol) of the residue was used in the following step.

1.0 g (0.92 mmol) of this residue, 75 μl (0.55 mmol) of triethylamineand Cosmosil 150 NH₂ -300 (having 450 μmol of amino groups per 1 g ofthe silica gel surface; produced by Nacalai Tesque Co. Ltd.) were addedto 20 ml of dimethylformamide. The resulting mixture was then stirred atroom temperature for 20 hours. The desired carrier, namely substitutedCosmosil 150 NH₂ -300 was collected, washed with methylene chloride anddried by evaporation under reduced pressure. 10 ml each of Cap A and Bsolutions (Nippon Millipore limited) were added to the carrier, and themixture was left to stand for 10 minutes. The mixture was then washedwith pyridine and with methylene chloride, in that order, and dried byevaporation under reduced pressure, to give the title compound.

The amount of the compound of Preparation 1 introduced into the titlecompound was determined according to the following method. A deblocksolution (a 3% v/v solution of dichloroacetic acid in methylenechloride, Nippon Millipore Limited) was added to 5.4 mg of the titlecompound, and the mixture was shaken for 3 minutes, after whichsufficient methylene chloride was added to make up a total amount of 20ml. 0.4 ml of the solvent was distilled off under reduced pressure, and3 ml of a 3:2 by volume solution of perchloric acid in ethanol was addedto the residue, and the absorbance of the dimethoxytrityl cation at 500nm was measured (ε=71700).

The amount of dimethoxytrityl groups introduced was found to be 51.8μmol/g.

Preparation 6 A Compound of Formula 6(p): ##STR92##

1.60 g (2.87 mmol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethyl monosuccinate (preparedas described in Preparation 1) were dissolved in 18 ml ofdimethylformamide, and 0.96 g (3.6 mmol) of pentachlorophenol and 0.96 g(4.5 mmol) of 1,3-dicyclohexylcarbodiimide were added to the solution.The resulting mixture was then stirred at room temperature for 18 hours.At the end of this time, precipitates were filtered off from thereaction mixture and the filtrate was freed from the solvent bydistillation under reduced pressure. Benzene was added to the residue.The resulting precipitates were filtered off and the filtrate was freedfrom the solvent by distillation under reduced pressure. 0.48 g (0.6mmol) of the residue were used in the following step.

0.48 g (0.6 mmol) of this residue, 110 mg (0.9 mmol) of4-(dimethylamino)pyridine and 1.0 g of a p-alkoxybenzyl alcohol resin(having 0.9 mmol of amino groups per 1 g of the silica gel surface;produced by Kokusan Kagaku Co. Ltd.) were added to 15 ml ofdimethylformamide, and the resulting mixture was stirred at roomtemperature for 25 hours. At the end of this time, the desired carrier,namely the substituted p-alkoxybenzyl alcohol resin was collected,washed with methylene chloride, with methanol and with diethyl ether, inthat order, and dried under by evaporation reduced pressure. 10 ml eachof Cap A and B solutions (Nippon Millipore Limited) were added to thecarrier, and the mixture was left to stand for 15 minutes. The mixturewas then washed with methylene chloride, with methanol and with diethylether, in that order, and dried by evaporation under reduced pressure,to give the title compound.

The amount of the compound of Preparation 1 introduced into the titlecompound was determined according to the following method. A deblocksolution (a 3% v/v solution of dichloroacetic acid in methylenechloride, Nippon Millipore Limited) was added to 10.6 mg of the titlecompound, and the mixture was shaken for 3 minutes, after whichsufficient methylene chloride was added to make up a total amount of 20ml. 0.4 ml of the solvent was distilled off, and then 6 ml of a 3:2 byvolume solution of perchloric acid in ethanol were added to the residue,and the absorbance of the dimethoxytrityl cation at 500nm was measured(ε=71700).

The amount of dimethoxytrityl groups introduced was found to be 302μmol/g.

Preparation 7 A Compound of Formula 7(p): ##STR93##

9.9 g (3.3 mmol) of poly(oxyethylene) diglycol were dried by azeotropicdistillation with pyridine and then dissolved in 10 ml of methylenechloride. 226 mg (1.1 mmol) of 1,3-dicyclohexylcarbodiimide were thenadded to the solution, whilst ice-cooling. The resulting mixture wasthen stirred whilst ice-cooling for 15 minutes. At the end of this time,2 ml of a methylene chloride solution containing 0.5 g (1.1 mol) of 2-2-O-(4,4'-dimethoxytrityloxy)ethylsulfonyl!ethanol Tetrahedron Lett.,27, 4705 (1986)! and 0.13 g (1.1 mmol) of 4-(dimethylamino)pyridine wereadded to the solution. The resulting mixture was stirred at roomtemperature for 18 hours. Precipitates were filtered off. The reactionmixture was then concentrated to 50 ml by evaporation under reducedpressure. 500 ml of cold diethyl ether were then added to theconcentrated solution, and the precipitates obtained were collected anddried by evaporation under reduced pressure. The resulting precipitateswere dissolved in methylene chloride and purified by columnchromatography through 200 g of silica gel (70-230 mesh) using a 2:8 byvolume mixture of methanol and methylene chloride as the eluent, to give2.77 g (yield 72%) of the title compound.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, TMS), δ ppm:7.09-7.43 (multiplet); 6.81-6.88 (multiplet); 4.58-4.64 (multiplet);3.65 (singlet); 3.50-3.53 (multiplet); 3.46-3.49 (multiplet); 3.31-3.34(multiplet).

Preparation 8 A Compound of Formula 8(p): ##STR94##

0.7 g (0.2 mmol) of the compound of Preparation 7 was dissolved in 6 mlof methylene chloride, and 2 ml of a dimethylformamide solutioncontaining 63 mg (0.24 mmol) of pentachlorophenol and 64 mg (0.3 mmol)of 1,3-dicyclohexylcarbodiimide were added to the solution, whilstice-cooling. The resulting solution was then stirred at room temperaturefor 7 days. At the end of this time, precipitates were filtered off fromthe reaction mixture, and the filtrate was freed from the solvent bydistillation under reduced pressure. The resulting residue was dissolvedin 10 ml of methylene chloride. 100 ml of diethyl ether were added tothe solution, whilst ice-cooling, and the resulting precipitates werefiltered off. The filtrate was freed from the solvent by distillationunder reduced pressure. The filtrate, 37 mg (0.3 mmol) of4-(dimethylamino)pyridine and 0.25 g of a p-alkoxybenzyl alcohol resin(having 0.9 mmol of amino groups per 1 g of the silica gel surface;produced by Kokusan Kagaku Co. Ltd.) were added to 6 ml ofdimethylformamide. The resulting mixture was left at room temperaturefor 24 hours. The desired carrier, namely a substituted p-alkoxybenzylalcohol resin was collected, washed with pyridine, with methylenechloride and with diethyl ether, in that order, and dried by evaporationunder reduced pressure. 10 ml each of Cap A and B solutions (NipponMillipore limited) were added to the carrier, and the mixture was leftto stand for 15 minutes. The mixture was then washed with methylenechloride, with methanol and with diethyl ether, in that order, and driedby evaporation under reduced pressure, to give the title compound.

The amount of the compound of Preparation 1 introduced into the titlecompound was determined according to the following method. A deblocksolution (a 3% v/v solution of dichloroacetic acid in methylenechloride, Nippon Millipore Limited) was added to 6.7 mg of the titlecompound, and the mixture was shaken for 3 minutes, after whichsufficient methylene chloride was added to make up a total amount of 20ml. 0.4 ml of the solvent was removed by distillation under reducedpressure, and then 20 ml of a 3:2 by volume solution of perchloric acidin ethanol were added to the residue, and the absorbance of thedimethoxytrityl cation at 500 nm was measured (ε=71700).

The amount of dimethoxytrityl groups introduced was found to be 16μmol/g

FORMULATION EXAMPLE 1 Injection Formulation

An injection formulation was prepared by stirring 1.5% by weight of thecompound of Example 25 in 10% by volume of propylene glycol, addingsufficient water for injections to give the required final volume andsterilizing.

FORMULATION EXAMPLE 2 Tablet Formulation

1) Compound of Example 25 200

2) Sodium pyrophosphate 5

3) Aerosil 200 5

4) Magnesium stearate 5

5) Lactose 495

6) Corn starch 154

7) Apicel 123

8) HPL (L) 10

Total 997 mg

Tablets, each containing 100 mg of the ingredients, were prepared byadding a ground mixture of the above Items No. 1 through 4 to apregranulated mixture of Items No. 5 through 8 and then compressing themixture produced above on a suitable tabletting machine.

FORMULATION EXAMPLE 3 Capsule Formulation

1) Compound of Example 25 200

2) Calcium phosphate 200

3) Aluminium silicate 345

4) Crystalline cellulose 250

5) Magnesium stearate 2

Total 997 mg

According to conventional means, capsules comprising 200 mg of the aboveingredients were prepared by pulverizing a mixture of the ingredients ina suitable mixer, passing the mixture through a screen and finallymixing well.

FORMULATION EXAMPLE 4 Hard Capsule Formulation

Unit capsules were prepared by mixing 100 mg of the powdery compound ofExample 25, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate, filling the above mixture into standard 2-piece hard gelatincapsules, washing and finally drying.

FORMULATION EXAMPLE 5 Soft Capsule Formulation

Soft capsules comprising 100 mg of the active ingredient were preparedby mixing the compound of Example 25 in a digestible oil (such as soybean oil, cottonseed oil or olive oil), filling this mixture intosuitable gelatine capsules by means of a motor pump, washing and finallydrying.

FORMULATION EXAMPLE 6 Tablet Formulation

According to conventional means, tablets were prepared by granulating amixture of 100 mg of the compound of Example 25, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of fine crystallinecellulose, 11 mg of starch and 98.8 mg of lactose.

    ______________________________________                                        Sequence table                                                                ______________________________________                                                 SEQ ID No. 1                                                                  Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGG                                                                SEQ ID No.: 2                                                                 Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGG                                                               SEQ ID No.: 3                                                                 Sequence length: 3                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical Sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGA                                                               SEQ ID No.: 4                                                                 Sequence length: 6                                                            Sequence type: Nucleic acid.                                                  Strandedness: Single                                                          Topology: Linear                                                              Hypothetical Sequence: No                                                     Anti-sesce: No                                                                Sequence: TGGGAG                                                              SEQ ID No.: 5                                                                 Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sesce: No                                                                Sequence: TGGGAGG                                                             SEQ ID No.: 6                                                                 Sequence length: 7.                                                           Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Hypothetical sequence: No                                                     Sequence: CGGGAGG                                                             SBQ ID No.: 7                                                                 Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCGAGG                                                             SEQ ID No.: 8                                                                 Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCGAGG                                                             SEQ ID No.: 9                                                                 Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: GGGGAGG                                                             SEQ ID No.: 10                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: mCGGGAGG                                                            SEQ ID No.: 11                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: mCGmCGAGG                                                           SEQ ID No.: 12                                                                Sequence length: 8                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTGGGAGG                                                            SEQ ID No.: 13                                                                Sequence length: 8                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTGGGAGG                                                            SEQ ID No.: 14                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTCGT                                                               SEQ ID No.: 15                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTCGC                                                               SEQ ID No.: 16                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTCGG                                                               SEQ ID No.: 17                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGGGT                                                               SEQ ID No.: 18                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGGGC                                                               SEQ ID No.: 19                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGGGG                                                               SEQ ID No.: 20                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGCGT                                                               SEQ ID No.: 21                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGCGC                                                               SEQ ID No.: 22                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGCGG                                                               SEQ ID No.: 23                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTGGA                                                               SEQ ID No.: 24                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTGGT                                                               SEQ ID No.: 25                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTGGC                                                               SEQ ID No.: 26                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTGGG                                                               SEQ ID No.: 27                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTCGA                                                               SEQ ID No.: 28                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTCGT                                                               SEQ ID No.: 29                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTCGC                                                               SEQ ID No.: 30                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTCGG                                                               SEQ ID No.: 31                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGT                                                               SEQ ID No.: 32                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGC                                                               SEQ ID No.: 33                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCGA                                                               SEQ ID No.: 34                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCGT                                                               SEQ ID No.: 35                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCGC                                                               SEQ ID No.: 36                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCGG                                                               SEQ ID No.: 37                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTGGT                                                               SEQ ID No.: 38                                                                Sequence length: 5                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTGGC                                                               SEQ ID No.: 39                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTCG                                                                SEQ ID No.: 40                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTCG                                                                SEQ ID No.: 41                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CTGG                                                                SEQ ID No.: 42                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGCG                                                                SEQ ID No.: 43                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGCG                                                                SEQ ID No.: 44                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CGGG                                                                SEQ ID No.: 45                                                                Sequence length: 4                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TTGG                                                                SEQ ID No.: 46                                                                Sequence length: 9                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: GGGCGGGGC                                                           SEQ ID No.: 47                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TAGGAGG                                                             SEQ ID No.: 48                                                                Sequence length: 8                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGAGGT                                                            SEQ ID No.: 49                                                                Sequence length: 9                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGCGCAG                                                           SEQ ID No.: 50                                                                Sequence length: 3                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: CCG                                                                 SEQ ID No.: 51                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TCGGAGG                                                             SEQ ID No.: 52                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGmCGAGG                                                            SEQ ID No.: 53                                                                Sequence length: 8                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: GTGGGAGG                                                            SEQ ID No.: 54                                                                Sequence length: 3                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGG                                                                 SEQ ID No.: 55                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGAmGG                                                            SEQ ID No.: 56                                                                Sequence length: 7                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: TGGGAGA                                                             SEQ ID No.: 57                                                                Sequence length: 9                                                            Sequence type: Nucleic acid                                                   Strandedness: Single                                                          Topology: Linear                                                              Hypothetical sequence: No                                                     Anti-sense: No                                                                Sequence: AATGGGAGG                                                  ______________________________________                                    

We claim:
 1. A method for the treatment of a HIV infection in a mammal,which method comprises administering to said mammal an amount of atleast one compound of the formula (1) which is effective for inhibitingthe replication of foreign nucleic acids in normal cells: ##STR95##wherein: R₁, R₂ and R are independently selected from the groupconsisting of hydrogen atoms, alkyl groups having from 1 to 4 carbonatoms, aryl groups as defined below, and anthraquinonyl groups which areunsubstituted or are substituted by at least one substituent selectedfrom the group consisting of substituents (a) defined below;Z representsa carbon atom or a silicon atom; or R₂, R₃ and Z together represent afluorenyl or xanthenyl group; R₄ represents a hydrogen atom, anunsubstituted alkyl group having from 1 to 4 carbon atoms, a substitutedalkyl group which has from 1 to 4 carbon atoms and which is substitutedby at least one substituent selected from the group consisting ofsubstituents (b) defined below, an aryl group as defined below, or anaralkyl group as defined below; Y₁, Y₃ and Y₄ are independently selectedfrom the group consisting of oxygen atoms, sulfur atoms and groups offormula >NH; Y₂ represents an oxygen atom, a sulfur atom, a group offormula >NH, an alkylene group having from 1 to 4 carbon atoms, or aphenylene group; X represents an unsubstituted alkylene group havingfrom 1 to 10 carbon atoms, or an alkylene group which has from 1 to 10carbon atoms and which is substituted by at least one hydroxy group; mand n is each independently 0 or an integer from 1 to 10; and Brepresents an oligodeoxyribonucleotide having a chain length of from 3to 9; said aryl group is an aromatic carbocyclic group which has from 6to 20 ring carbon atoms and which is unsubstituted or is substituted byat least one substituent selected from the group consisting ofsubstituents (a) defined below; said aralkyl group is an alkyl groupwhich has from 1 to 4 carbon atoms and which is substituted by at leastone aryl group as defined above; said substituents (a are selected fromthe group consisting of alkyl groups having from 1 to 4 carbon atoms,haloalkyl groups having from 1 to 4 carbon atoms, halogen atoms, nitrogroups, cyano groups, amino groups, alkoxy groups having from 1 to 4carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, arylgroups as defined above, aryloxy groups in which the aryl part is asdefined above, and aralkyloxy groups in which the aralkyl part is asdefined above, provided that, where said substituent (a) represents anaryl group or a group containing an aryl group which is substituted by afurther aryl group or group or group containing an aryl group, thatfurther group is not itself substituted by an aryl group or a groupcontaining an aryl group; and said substituents (b) are selected fromthe group consisting of amino groups, alkoxy groups having from 1 to 4carbon atoms, and halogen atoms; or a salt thereof.
 2. The method ofclaim 1, wherein the oligodeoxyribonucleotide B has a chain length of 4to
 8. 3. The method of claim 2, wherein the oligodeoxyribonucleotide Bhas a chain length of 5 or
 6. 4. The method of claim 1, wherein thegroup of formula R₁ R₂ R₃ Z-Y₁ is selected from the group consisting ofa triphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy,3,5-(dibenzyloxy)benzyloxy, 3,5-bis3,5-(dibenzyloxy)benzyloxy!benzyloxy, tert-butyldiphenylsilyloxy,phenylfluorenyloxy and phenylxanthenyloxy group; the group of formulaP(O)(Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H is selected from the groupconsisting of a hydrogen atom, a methylphosphoryl,2-chlorophenylphosphoryl, O-methylthiophosphoryl, methylphosphonyl,methylthiophosphonyl, phenylphosphonyl, 2-hydroxyethylphosphoryl,-O-(2-hydroxyethyl)thiophosphoryl, phenylphosphoryl,4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl and -O-ethylthiophosphorylgroup; and B is selected from the group consisting of TGGGAG, TGGGA,TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG, TTGGGAGG, TGCGAGG, GGGGAGG,mCGGGAGG, mCGmCGAGG, CTGGGAGG, GGGCGGGGC, TAGGAGG, TGGGAGGT, TGGGCGCAG,CCG, TCGGAGG, TGmCGAGG, CTGGGAGG, TGG, TGGGAmGG, TGGGAGA, AATGGGAGG,TTGGGG, TGGGGG, CGGGG, CGCGG, CGGGT, TGGGC and TGGGT.
 5. The method ofclaim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ is selected from thegroup consisting of a triphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy,3,5-(dibenzyloxy)benzyloxy,3,5-bis(3,5-(dibenzyloxy)benzyloxylbenzyloxy,tert-butyldiphenylsilyloxy, phenylfluorenyloxy and phenylxanthenyloxygroup; the group of formula P(O) (Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H isselected from the group consisting of a hydrogen atom, amethylphosphoryl, 2-chlorophenylphosphoryl, -O-methylthiophosphoryl,methylphosphonyl, methylthiophosphonyl, phenylphosphonyl,2-hydroxyethylphosphoryl, -O-(2-hydroxyethyl)thiophosphoryl,phenylphosphoryl, 4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl and -O-ethylthiophosphorylgroup; and B is selected from the group consisting of TGGGAG, TGGGA,TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG, TTGGGAGG, TGCGAGG, GGGGAGG,mCGGGAGG, mCGmCGAGG, CTGGGAGG, TTGGGG, TGGGGG, CGGGG and CGCGG.
 6. Themethod of claim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ isselected from the group consisting of a triphenylmethyloxy,3,4-(dibenzyloxy)benzyloxy, 3,5-(dibenzyloxy)benzyloxy, 3,5-bis3,5-(dibenzyloxy)benzyloxy!benzyloxy, tert-butyldiphenylsilyloxy,phenylfluorenyloxy and phenylxanthenyloxy group; the group of formula P(O)(Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H is selected from the groupconsisting of a hydrogen atom, a methylphosphoryl,2-chlorophenylphosphoryl, -O-methylthiophosphoryl, methylphosphonyl,methylthiophosphonyl, phenylphosphonyl, 2-hydroxyethylphosphoryl and-O-(2-hydroxyethyl)thiophosphoryl group; and B is selected from thegroup consisting of TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG,TTGGAGG, TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG,TTGGGG, TGGGGG, CGGGG and CGCGG.
 7. The method of claim 1, wherein thegroup of formula R₁ R₂ R₃ Z-Y₁ is selected from the group consisting ofa triphenylmethyloxy, 3,4-(dibenzyloxy)benzyloxy and3,5-(dibenzyloxy)benzyloxy group; the group of formula (P(O)(Y₂ R₄)--Y₃--(X--Y₄)_(n) !_(m) H is selected from the group consisting of ahydrogen atom, a methylphosphoryl, 2-chlorophenylphosphoryl,-O-methylthiophosphoryl, methylphosphonyl, methylthiophosphonyl,phenylphosphonyl, 2- hydroxyethylphosphoryl,-O-(2-hydroxyethyl)thiophosphoryl, phenylphosphoryl,4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl and -O-ethylthiophosphorylgroup; and B is selected from the group consisting of TGGGAG, TGGGA,TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG, TTGGGAGG TGCGAGG, GGGGAGG,mCGGGAGG, mCGmCGAGG, CTGGGAGG, TTGGGG, TGGGGG, CGGGG and CGCGG.
 8. Themethod of claim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ isselected from the group consisting of a triphenylmethyloxy,3,4-(dibenzyloxy)benzyloxy and 3,5-(dibenzyloxy)benzyloxy group; thegroup of formula P(O)((Y₂ R₄)--Y₃ --(X--Y₄)_(n) !_(m) H is selected fromthe group consisting of a hydrogen atom, a methylphosphoryl,2-chlorophenylphosphoryl, -O-methylthiophosphoryl, methylphosphonyl,methylthiophosphonyl, phenylphosphonyl, 2-hydroxyethylphosphoryl and-O-(2-hydroxyethyl)thiophosphoryl group; and B is selected from thegroup consisting of TGGGAG, TGGGA, TGGGG, TGGG, TGGGAGG, CGGGAGG,TTGGAGG, TTGGGAGG, TGCGAGG, GGGGAGG, mCGGGAGG, mCGmCGAGG, CTGGGAGG,TTGGGG, TGGGGG, CGGGG and CGCGG.
 9. The method of claim 1, wherein thegroup of formula R₁ R₂ R₃ Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxygroup; Y₂ represents an oxygen atom; Y₃ represents an oxygen atom; Y₄represents an oxygen atom; R₄ represents a hydrogen atom; X representsan ethylene group; m represents 1; n represents 1; and B representsTGGGAG.
 10. The method of claim 1, wherein the group of formula R₁ R₂ R₃Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxy group; Y₂ represents asulfur atom; Y₃ represents an oxygen atom; Y₄ represents an oxygen atom;R₄ represents a hydrogen atom; X represents an ethylene group; mrepresents 1; n represents 1; and B represents TGGGAG.
 11. The method ofclaim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ represents a3,4-(dibenzyloxy)benzyloxy group; m represents 0; n represents 0; and Brepresents TGGGAG.
 12. The method of claim 1, wherein the group offormula R₁ R₂ R₃ Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxy group; Y₂represents an oxygen atom; Y₃ represents an oxygen atom; R₄ represents amethyl group; m represents 1; n represents 0; and B represents TGGGAG.13. The method of claim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁represents a triphenylmethyloxy group; Y₂ represents an oxygen atom; Y₃represents an oxygen atom; Y₄ represents an oxygen atom; R₄ represents ahydrogen atom; X represents an ethylene group; m represents 1; nrepresents 1; and B represents TGGGAG.
 14. The method of claim 1,wherein the group of formula R₁ R₂ R₃ Z-Y₁ represents atriphenylmethyloxy group; Y₂ represents a sulfur atom; Y₃ represents anoxygen atom; Y₄ represents an oxygen atom; R₄ represents a hydrogenatom; X represents an ethylene group; m represents 1; n represents 1;and 3 represents TGGGAG.
 15. The method of claim 1, wherein the group offormula R₁ R₂ R₃ Z-Y₁ represents a triphenylmethyloxy group; mrepresents 0; n represents 0; and B represents TGGGAG.
 16. The method ofclaim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ represents atriphenylmethyloxy group; Y₂ represents an oxygen atom; Y₃ represents anoxygen atom; R₄ represents a methyl group; m represents 1; n represents0; and B represents TGGGAG.
 17. The method of claim 1, wherein the groupof formula R₁ R₂ R₃ Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxy group;Y₂ represents an oxygen atom; Y₃ represents an oxygen atom; Y₄represents an oxygen atom; R₄ represents a hydrogen atom; X representsan ethylene group; m represents 1; n represents 1; and 3 representsCGGGG.
 18. The method of claim 1, wherein the group of formula R₁ R₂ R₃Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxy group; Y₂ represents asulfur atom; Y₃ represents an oxygen atom; Y₄ represents an oxygen atom;R₄ represents a hydrogen atom; X represents an ethylene group; mrepresents 1; n represents 1; and B represents CGGGG.
 19. The method ofclaim 1 wherein the group of formula R₁ R₂ R₃ Z-Y₁ represents a3,4-(dibenzyloxy)benzyloxy group; m represents 0; n represents 0; and Brepresents CGGGG.
 20. The method of claim 1, wherein the group offormula R₁ R₂ R₃ Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxy group; Y₂represents an oxygen atom; Y₃ represents an oxygen atom; R₄ represents amethyl group; m represents 1; n represents 0; and B represents CGGGG.21. The method of claim 1 wherein the group of formula R₁ R₂ R₃ Z-Y₁represents a triphenylmethyloxy group; Y₂ represents an oxygen atom; Y₃represents an oxygen atom; Y₄ represents an oxygen atom; R₄ represents ahydrogen atom; X represents an ethylene group; m represents 1; nrepresents 1; and B represents CGGGG.
 22. The method of claim 1, whereinthe group of formula R₁ R₂ R₃ Z-Y₁ represents a triphenylmethyloxygroup; Y₂ represents a sulfur atom; Y₃ represents an oxygen atom; Y₄represents an oxygen atom; R₄ represents a hydrogen atom; X representsan ethylene group; m represents 1; n represents 1; and B representsCGGGG.
 23. The method of claim 1, wherein the group of formula R₁ R₂ R₃Z-Y₁ represents a triphenylmethyloxy group; m represents 0; n represents0; and B represents CGGGG.
 24. The method of claim 1, wherein the groupof formula R₁ R₂ R₃ Z-Y₁ represents a triphenylmethyloxy group; Y₂represents an oxygen atom; Y₃ represents an oxygen atom; R₄ represents amethyl group; m represents 1; a represents 0; and B represents CGGGG.25. The method of claim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁represents a 3,4-(dibenzyloxy)benzyloxy group; Y₂ represents an oxygenatom; Y₃ represents an oxygen atom; Y₄ represents an oxygen atom; R₄represents a hydrogen atom; X represents an ethylene group; m represents1; n represents 1; and B represents CGCGG.
 26. The method of claim 1,wherein the group of formula R₁ R₂ R₃ Z-Y₁ represents a3,4-(dibenzyloxy)benzyloxy group; Y₂ represents a sulfur atom; Y₃represents an oxygen atom; Y₄ represents an oxygen atom; R₄ represents ahydrogen atom; X represents an ethylene group; m represents 1; nrepresents 1; and B represents CGCGG.
 27. The method of claim 1, whereinthe group of formula R₁ R₂ R₃ Z-Y₁ represents a3,4-(dibenzyloxy)benzyloxy group; m represents 0; n represents 0; and Brepresents CGCGG.
 28. The method of claim 1, wherein the group offormula R₁ R₂ R₃ Z-Y₁ represents a 3,4-(dibenzyloxy)benzyloxy group; Y₂represents an oxygen atom; Y₃ represents an oxygen atom; R₄ represents amethyl group; m represents 1; n represents 0; and 3 represents CGCGG.29. The method of claim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ is3,4-(dibenzyloxy)benzyloxy and B is TGGGAG.
 30. The method of claim 29,wherein Y₂ is a sulfur atom or an oxygen atom; R₄ is a hydrogen atom oran alkyl group having 1 to 4 carbon atoms; Y₃ is a sulfur atom or anoxygen atom; X is an alkylene group having 1 to 10 carbon atoms; Y₄ isan oxygen atom; n is 0 or 1 and m is
 1. 31. The method of claim 1,wherein the group of formula R₁ R₂ R₃ Z-Y₁ is a3,4-(dibenzyloxy)benzyloxy group; Y₂ is an oxygen atom; Y₃ is a sulfuratom; R₄ is a methyl group; m represents 1; n is zero, and B is TGGGAG.32. The method of claim 1, wherein the group of formula R₁ R₂ R₃ Z-Y₁ isa 3,4-(dibenzyloxy)benzyloxy group; Y₂ is an oxygen atom; Y₃ is anoxygen atom; R₄ is a hydrogen atom; m is 1; n is zero, and B is TGGGAG.33. A composition for the treatment of HIV infection, which comprises anamount of at least one compound of the following formula (1) which iseffective for inhibiting the replication of foreign nucleic acids innormal cells: ##STR96## wherein the group of formula R₁ R₂ R₃ Z-Y₁ isselected from the group consisting of a triphenylmethyloxy,3,4-(dibenzyloxy)benzyloxy, 3,5-(dibenzyloxy)benzyloxy,3,5-bis(3,5-(dibenzyloxy)benzyloxy)benzyloxy,tert-butyldiphenylsilyloxy, phenylfluorenyloxy and phenylxanthenyloxygroup; the group of formula (P(O) (Y₂ R₄)--Y₃ --(X--Y₄)_(n))_(m) H isselected fromthe group consisting of a hydrogen atom, amethylphosphoryl, 2-chlorophenylphosphoryl, -O-methylthiophosphonyl,methylphosphonyl, methylthiophosphonyl, phenylphosphonyl,2-hydroxyethylphosphoryl, -O-(2-hydroxyethyl)thiophosphoryl,phenylphosphoryl, 4-chlorophenylphosphoryl, 2-nitrophenylphosphoryl,4-nitrophenylphosphoryl, ethylphosphoryl and -O-ethylthiophosphorylgroup; and 2 is selected from the group consisting of TGGGAG, TGGGA,TGGGG, TGGG, TGGGAGG, CGGGAGG, TTGGAGG, TTGGGAGG, TGCGAGG, GGGGAGG,mCGGGAGG, mCGmCGAGG, CTGGGAGG, GGGCGGGGC, TAGGAGG, TGGGAGGT, TGGGCGCAG,CCG, TCGGAGG, TGmCGAGG, CTGGGAGG, TGG, TGGGAmGG, TGGGAGA, AATGGGAGG,TTGGGG, TGGGGG, CGGGG, CGCGG, CGGGT, TGGGC, and TGGGT, wherein mC is5-methylcytosinedeoxyribonucleotide; and mG is O⁶-methylguaninedeoxyribonucleotide, in combination with a carrier. 34.The composition of claim 33, wherein the group R₁ R₂ R₃ Z-Y₁ is3,4-(dibenzyloxy)benzyloxy, n is TGGGAG and the group P(O)(Y₂ R₄)--Y₃--(X--Y₄)_(n))_(m) H is 2-hydroxyethylphosphoryl.
 35. The composition ofclaim 33, wherein the group R₁ R₂ R₃ Z-Y₁ is 3,4-(dibenzyloxy)benzyloxyand B is TGGGAG.